JP4604086B2 - RAF modulator and method of using the same - Google Patents

Description

(Background of the Invention)
(Cross-reference of related applications)
This application claims priority from US Provisional Application No. 60 / 569,009, filed May 7, 2004. The contents of this priority application are hereby incorporated by reference in their entirety.

(Field of Invention)
The present invention relates to compounds that modulate protein kinase enzyme activity to modulate cellular activities such as proliferation, differentiation, programmed cell death, migration and chemical invasion. Even more specifically, the present invention relates to compounds that inhibit, regulate and / or modulate kinases, particularly Raf. Kinase receptor signaling pathways associated with changes in cellular activity as described above are modulated using the compounds of the present invention. Methods of using the compounds to treat kinase dependent diseases and conditions are also embodiments of the invention.

(Overview of related technologies)
Improvements in the specificity of drugs used to treat cancer have considerable interest for the therapeutic benefits that would be realized if the side effects associated with the administration of these drugs can be reduced. It is. Traditionally, dramatic improvements in the treatment of cancer are associated with the identification of therapeutic agents that act by novel mechanisms.

  Protein kinases are enzymes that catalyze the phosphorylation of hydroxy groups on proteins, particularly tyrosine, serine and threonine residues of proteins. This seemingly simple activity result is staggering; cell differentiation and proliferation; that is, virtually all aspects of cell life are in each case dependent on protein kinase activity. Furthermore, abnormal protein kinase activity has been associated with a host of many diseases, ranging from relatively life-threatening diseases such as psoriasis to highly malignant diseases such as glioblastoma (brain cancer).

  Protein kinases can be classified as receptor type or non-receptor type. Receptor type tyrosine kinases have an extracellular portion, an intramembrane portion, and an intracellular portion, while non-receptor type tyrosine kinases are entirely intracellular.

  Receptor type tyrosine kinases are composed of many transmembrane receptors with diverse biological activities. Receptor type tyrosine kinases have, in fact, been identified in about 20 different subfamilies. One tyrosine kinase subfamily, called the HER subfamily, is composed of EGFR (HER1), HER2, HER3, and HER4. Receptor ligands of this subfamily identified to date include epidermal growth factor, TGF-α, amphiregulin, HB-EGF, betacellulin and heregulin. Another subfamily of these receptor type tyrosine kinases is the insulin subfamily, including INS-R, IGF-IR, and IR-R. The PDGF subfamily includes PDGF-α and PDGF-β receptors, CSFIR, c-kit and FLK-II. Furthermore, there is a FLK family consisting of kinase insertion domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and fms-like tyrosine kinase-1 (flt-1). is there. The PDGF family and FLK family are usually considered together because of the similarity of the two groups. For a detailed discussion of receptor type tyrosine kinases, see Non-Patent Document 1, which is incorporated herein by reference.

  The non-receptor types of tyrosine kinases also consist of many subfamilies such as Src, Frk, Btk, Csk, AbI, Zap70, Fes / Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further subdivided into various receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes is associated with carcinogenesis. For a more detailed discussion of non-receptor type tyrosine kinases, see Non-Patent Document 2, which is incorporated herein by reference.

  Since protein kinases and their ligands play an important role in various cellular activities, deregulation of protein kinase enzyme activity can lead to changes in cellular properties such as uncontrolled cell growth associated with cancer. In addition to oncological indicators, alterations in kinase signaling are associated with many other pathological diseases. These include, but are not limited to, immunological disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases. Thus, both receptor and non-receptor protein kinases are attractive targets for small molecule drug discovery.

  One particularly attractive goal for therapeutic use of kinase modulation is for oncological indicators. For example, by FDA approval of Gleevec® (imatinib mesylate manufactured by Novartis Pharmaceutical, Inc., East Hanover, NJ) for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal cancer Regulation of protein kinase activity for the treatment of cancer has been successfully demonstrated. Gleevec is a selective Ab1 kinase inhibitor.

  Two important cellular processes necessary for tumor growth and survival, regulation (particularly inhibition) of cell growth and angiogenesis (3) are attractive targets for small molecule drug development. Anti-angiogenic therapy may be an important approach for the treatment of solid tumors and other diseases associated with dysregulation of angiogenesis such as ischemic coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis is there. Cell anti-proliferation agents are also desirable to delay or stop tumor growth.

One particularly attractive target for small molecule modulation of anti-angiogenic and anti-proliferative activities is Raf. The Raf-MEK-ERK signaling cascade is a conserved pathway that regulates cell growth, proliferation, differentiation, and apoptosis in response to growth factor cytokines and hormones. This pathway is often up-regulated in human tumors or acts downstream of mutated Ras. Raf has proven to be an important effector of Ras function. Activated Ras mutants are present in a large proportion of human cancers such as 80% of pancreatic cancer, 50% of colorectal cancer and 40% of lung cancer. In addition, somatic mutations in the B-Raf gene are associated with 60% of malignant melanomas and occur frequently in ileorectal and papillary thyroid tumors. It has been shown that inhibition of the ERK pathway, particularly inhibition of Raf kinase activity, mainly leads to reduced cell-cell contact and motility, and down-regulation of vascular endothelial growth factor (VEGF) expression resulting in anti-metastatic effects and anti-angiogenesis. Has been. Furthermore, expression of predominantly inactive Raf, MEK or ERK reduced the ability of mutant Ras to transform as seen in primary and metastatic growth of cell culture and in vivo human tumor xenografts. Thus, the Raf-MEK-ERK signaling pathway is a suitable route as a target for therapeutic intervention.
Plowman et al., DN & P7 (6): (1994) 334-339. Bolen, Oncogene, 8: (1993) 2025-2031. Matter A. Drug Disc Technol (2001) 6, pages 1005-1024

  Accordingly, the identification of small molecule compounds that specifically inhibit, regulate and / or regulate kinases, particularly Raf, is desirable as a means of treating or preventing disease states associated with cancer and is an object of the present invention.

(Summary of Invention)
The present invention provides compounds that modulate kinase activity and methods of treating diseases mediated by kinase activity, particularly Raf, utilizing the compounds and pharmaceutical compositions thereof. Diseases mediated by kinase activity are those referred to herein as “kinase-dependent diseases or conditions” (see definitions in the Detailed Description of the Invention below). Inhibitors that are selective for Raf are included in the present invention.

  In another aspect, the present invention provides a screening method for modulators of kinase activity. The method comprises combining the composition of the invention, a kinase, and at least one candidate agent, and determining the effect of the candidate agent on kinase activity.

  In still other embodiments, the invention is also filled with one or more components of a pharmaceutical compound and / or a composition of the invention, such as one or more kinase enzyme activity modulators described herein. There is provided a pharmaceutical kit comprising one or a plurality of containers. Such kits also include, for example, other compounds and / or compositions (eg, diluents, permeation enhancers, lubricants, etc.), devices for administering the compounds and / or compositions, and drugs or organisms. Can include instructions for use in a form stipulated by a governmental authority that regulates the manufacture, use or sale of a biological product, the instructions also for manufacture, use or administration for human administration May reflect approval by sales authorities.

  In still yet another aspect, the present invention also provides a diagnostic agent comprising a compound of the present invention, and optionally pharmaceutically acceptable adjuvants and excipients.

  These and other features and advantages of the present invention are described in greater detail below.

(Detailed description of the invention)
The compositions of the invention are used to treat diseases associated with abnormal and / or uncontrolled cellular activity. Disease states that can be treated by the methods and compositions provided herein include, but are not limited to, cancer (discussed further below), rheumatoid arthritis, graft host disease, multiple sclerosis, psoriasis Immunological disorders such as; cardiovascular diseases such as atherosclerosis, myocardial infarction, ischemia, pulmonary hypertension, heart attack and restenosis; Other inflammatory and degenerative diseases are included.

  It is recognized that the cells are not over-proliferated or under-proliferated and / or migratory (abnormal), but may still require treatment. For example, during wound healing, cells can proliferate “normally”, but enhanced proliferation and migration may be desirable. Alternatively, “normal” cell growth and / or reduced migration rate may be desirable.

  The present invention provides compounds of formula I that modulate kinase activity, particularly Raf,

Or a pharmaceutically acceptable salt, hydrate or prodrug thereof, provided that the compound is not CAS Registry Number 439096-29-4, 439107-32-1, or 439107-34-3 so;
Where
A is a 3- to 7-membered alicyclic, 5- to 6-membered ortho-arylene, or 5- to 6-membered ortho-containing between 1 and 3 heteroatoms. A heteroarylene, any of the foregoing is optionally substituted with up to 4 R;
Each R, -H, _{^{halogen, -CN, -NO 2, -OR 3}} , -N (R 3) R 3, -S (O) 0~2 R 3, -SO 2 N (R 3) R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R ³⁾ ) CO ₂ R ³ , —C (O) R ³ , —OC (O) R ³ , optionally substituted C _1-6 alkyl, optionally substituted aryl, optionally substituted aryl C Independently selected from _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle _C1-6 alkyl;
Any two R, together with the atoms to which they are attached, form a first ring system fused with A, wherein the first ring system is substituted with 0 to 3 R ¹ There;
X ₁ , X ₂ and X ₃ are independently selected from —CR ¹ ═ or —N═;
Each of R ¹ is —H, halogen, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —SO ₂ N (R ³ ). R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R _{^{3) CO 2 R 3, -C}} (O) R 3, -OC (O) R 3, aryl aryl, optionally substituted substituted _{C 1 to 6} alkyl, optionally substituted optionally Independently selected from C _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-6 alkyl;
Z and ^{X, -C (R 2) =,} - N =, - N (R 2) -, - S (O) 0~2 -, and each independently selected from -O-;
E and Y are each independently selected from absent, —C (R ² ) (R ² ) —, —C (═O) —, —C (R ² ) ═ and —N═, Y is not both absent, and when both Z and X are -N =, E and Y are not both -N =;
Each of R ² is R ³ , —N (R ³ ) R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) CO ₂ R ³ , —N (R ³ ) C ( Independently selected from O) N (R ³ ) R ³ , and —N (R ³ ) C (O) R ³ ;
Each of R ³ is —H, optionally substituted C _1-6 alkyl, optionally substituted C _3-7 alicyclic, optionally substituted aryl, optionally substituted aryl Independently selected from C _1-3 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-3 alkyl;
Any two R ³ , when taken together with the common nitrogen to which they are attached, form an optionally substituted 5- to 7-membered heterocycle, said optionally substituted The 5- to 7-membered heterocycle optionally contains at least one additional heteroatom selected from N, O, S, and P;
G is —CO ₂ R ³ , —C (O) R ³ , —C (O) N (R ³ ) R ³ , —C (O) (NR ³ ), —C (O) NR ³ [C ( R ³ ) ₂ ] _0-1 R ³ , —C (O) NR ³ O [C (R ³ ) ₂ ] _0-1 R ³ , —N (R ³ ) CO ₂ R ³ , —N (R ³ ) ^{C (O) N (R 3} ) R 3, -N (R 3) C (O) R 3, -N (R 3) R 3, -S (O) 0~2 R 3, -SO 2 N ( R ³ ) selected from R ³ , optionally substituted aryl C _0-3 alkyl, and optionally substituted heterocycle C _0-3 alkyl.

  In one example, the compound is described in paragraph [0020] (of this International Publication) and A is a 6-membered orthoarylene.

  In one example, the compound is described in paragraph [0021] (of this International Publication Pamphlet) and A is ortho-phenylene.

In one example, the compound is described in paragraph [0022] (of this International Publication Pamphlet), wherein G is -C (O) R ³ , -C (O) N (R ³ ) R ³ , _{^{-C (O) (NR 3)}} , - C (O) NR 3 [C (R 3) 2] 0~1 R 3, -C (O) NR 3 O [C (R 3) 2] 0~1 it is R ^3.

In one example, the compound is described in paragraph [0023] (of this International Publication Pamphlet) and G is —C (O) N (R ³ ) R ³ .

In one example, the compound is described in paragraph [0024] (of this International Publication Pamphlet) and G is —C (O) NHR ³ .

In one example, the compound is described in paragraph [0025] (of this International Publication) and R ³ is an optionally substituted C _1-6 alkyl.

In one example, the compound is described in paragraph [0025] (of this international pamphlet) and R ³ is an optionally substituted aryl.

In one example, the compound is described in paragraph [0025] (of this International Publication) and R ³ is an optionally substituted aryl C _1-3 alkyl.

In one example, the compound is described in paragraph [0025] (of this International Publication) and R ³ is an optionally substituted heterocycle.

In one example, the compound is described in paragraph [0025] (of this International Publication Pamphlet) and R ³ is an optionally substituted heterocyclic C _1-3 alkyl.

In one example, the compound is described in paragraph [0025] (of this International Publication Pamphlet) and X ₁ , X ₂ and X ₃ are —CR ¹ ═.

  In one example, the compound is described in paragraph [0031] (of this international pamphlet) and E is absent.

In one example, the compound is (this International Publication Pamphlet) are described in paragraph [0032], Z is -N =; Y is -C ^(R 2) = a and; and X, Selected from —N (R ² ) —, —S—, and —O—.

  In one example, the compound is described in paragraph [0025] (of this international pamphlet) where it is recognized that the present invention encompasses the conversion of tautomers of each compound.

  In one example, the compound has the formula Ia:

In which R ³ , A, X ₁ , X ₂ , X ₃ , Z, E, Y and X are as defined above. As described in paragraph [0034] (of this international pamphlet).

  In one example, the compound is described in paragraph [0020] (of this International Publication Pamphlet) and the compound is a pharmaceutically acceptable salt.

  In one example, the compound is described in paragraph [0020] (of this international pamphlet) and the compound is a prodrug.

  The present invention relates to Formula II that modulates kinase activity, particularly Raf,

Or a pharmaceutically acceptable salt, hydrate or prodrug thereof, provided that the compound is not CAS Registry Number 439096-29-4, 439107-32-1, or 439107-34-3. In the formula
A is a 5- to 6-membered ortho-arylene or a 5- to 6-membered ortho-heteroarylene containing between 1 and 3 heteroatoms, and any of the foregoing is 4 Optionally substituted with up to two R;
Each R, -H, _{^{halogen, -CN, -NO 2, -OR 3}} , -N (R 3) R 3, -S (O) 0~2 R 3, -SO 2 N (R 3) R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R ³⁾ ) CO ₂ R ³ , —C (O) R ³ , —OC (O) R ³ , optionally substituted C _1-6 alkyl, optionally substituted aryl, optionally substituted aryl C Independently selected from _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle _C1-6 alkyl;
Any two R, together with the atoms to which they are attached, form a first ring system fused with A, wherein the first ring system is substituted with 0 to 3 R ¹ There;
n is 0 to 3;
Each of R ¹ is —H, halogen, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —SO ₂ N (R ³ ). R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R _{^{3) CO 2 R 3, -C}} (O) R 3, -OC (O) R 3, aryl aryl, optionally substituted substituted _{C 1 to 6} alkyl, optionally substituted optionally Independently selected from C _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-6 alkyl;
Z and ^{X, -C (R 2) =,} - N =, - N (R 2) -, - S (O) 0~2 -, and each independently selected from -O-;
E and Y are each independently selected from absent, —C (R ² ) (R ² ) —, —C (═O) —, —C (R ² ) ═ and —N═, Y is not both absent, and when both Z and X are -N =, E and Y are not both -N =;
Each of R ² is R ³ , —N (R ³ ) R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) CO ₂ R ³ , —N (R ³ ) C ( Independently selected from O) N (R ³ ) R ³ , and —N (R ³ ) C (O) R ³ ;
Each R ^3, -H, heterocycle substituted C _{1 to 6} alkyl which is optionally substituted, aryl which is optionally substituted, aryl C _{1 to 3} alkyl which is optionally substituted, optionally And optionally selected from optionally substituted heterocycle C _1-3 alkyl;
Any two R ³ , when taken together with the common nitrogen to which they are attached, form an optionally substituted 5- to 7-membered heterocycle, said optionally substituted The 5- to 7-membered heterocycle optionally contains at least one additional heteroatom selected from N, O, S, and P;
G ^{is, -C (O) R 3,} -C (O) N (R 3) R 3, -N (R 3) CO 2 R 3, -N (R 3) C (O) N (R 3) R ³ , —N (R ³ ) C (O) R ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —SO ₂ N (R ³ ) R ³ , optionally substituted Selected from aryl C _1-3 alkyl, and optionally substituted heterocyclic C _1-3 alkyl.

  In one example, the compound is described in paragraph [0038] (of this International Publication Pamphlet), where E is absent.

  In one example, the compound is described in paragraph [0039] (of this International Publication Pamphlet), where A is ortho-phenylene.

  In another example, the compound has formula III,

A compound described in paragraph [0040] of this international pamphlet,
Wherein Z, Y, and X are as defined above; G is —C (O) R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ). _{^{CO 2 R 3, -N (R}} 3) C (O) N (R 3) R 3, -N (R 3) C (O) R 3, -N (R 3) R 3, -SO 2 NR ( R ³ ) selected from R ³ , optionally substituted aryl C _1-3 alkyl, and optionally substituted heterocyclic C _1-3 alkyl; R is —H, halogen, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —SR ³ , —CO ₂ R ³ , and optionally substituted C _1-6 alkyl; R ¹ is —H, halogen, _{^{-CN, -NO 2, -OR 3,}} -N (R 3) R 3, -S (O) 0~2 R 3, -SO 2 N (R 3) R 3, -CO 2 R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R ³ ) CO ₂ R ³ , —C (O) R ³ , —OC (O) R ³ , optionally substituted C _1-6 alkyl, optionally substituted aryl, optionally substituted aryl C _1-6 alkyl, optional Selected from heterocycles substituted with and optionally substituted heterocycle C _1-6 alkyl.

In another example, the compound is described in paragraph [0041] (of this International Publication), Z is —N═; Y is —C (R ² ) ═; X is —N (R ² ) —, —S—, and —O— are selected.

In another example, the compound is described in paragraph [0042] (of this international pamphlet) and R and R ¹ are —H.

  In another example, the compound has formula IVa or IVb,

A compound described in paragraph [0043] of this international pamphlet,
G ^{is, -C (O) R 3,} -C (O) N (R 3) R 3, -N (R 3) CO 2 R 3, -N (R 3) C (O) N (R 3) R ³ , —N (R ³ ) C (O) R ³ , —N (R ³ ) R ³ , —SO ₂ N (R ³ ) R ³ , optionally substituted aryl C _1-3 alkyl, and Selected from optionally substituted heterocycle C _1-3 alkyl; R ³ is as defined above; R ² is —H or optionally substituted C _1-6 alkyl; And when R ² is —H or optionally substituted C _1-6 alkyl and all other groups are the same, R ² is —H and all other If the group is the same, of course IVa and IVb represent a tautomer of a single ^{molecule; R 3a} is -H or optionally is substituted Be either _{C 1 to 6} alkyl ^{and; R 3b} is aryl _{C 1 to 3} alkyl substituted _{C 1 to 6} alkyl which is optionally substituted, aryl which is optionally substituted, optionally, Selected from optionally substituted heterocycle and optionally substituted heterocycle C _1-3 alkyl.

In another example, the compound is described in paragraph [0044] (of this International Publication Pamphlet) and R ^3a is —H.

In another example, the compound is described in paragraph [0045] (of this International Publication Pamphlet) and R ² is —H.

In another example, the compound is described in paragraph [0046] (of this International Publication Pamphlet), where G is —C (O) R ³ , —C (O) N (R ³ ) R ³ , _{^{-N (R 3) CO 2 R}} 3, is selected from -N (R 3) C (O ) N (R 3) R 3, and ^{-N (R 3) C (O} ) R 3.

  In another example, the compound has the formula V,

A compound described in paragraph [0046] of this international publication pamphlet,
Wherein W is R ³ or —N (R ³ ) R ³ ; and R ^3b is optionally substituted C _1-6 alkyl, optionally substituted aryl, and optionally substituted. Selected from aryl C _1-3 alkyl.

In another example, the compound is described in paragraph [0048] (of this International Publication Pamphlet) and W is —N (H) R ³ .

In another example, the compound is described in paragraph [0049] (of this International Publication Pamphlet) and R ³ is optionally substituted aryl.

In another example, the compound is described in paragraph [0050] (of this international pamphlet) and R ^3b is an optionally substituted C _1-6 alkyl.

In another example, the compound is described in paragraph [0051] (of this International Publication) and R ^3b is C _1-6 alkyl.

  In another example, the compound is described in paragraph [0038] (of this international pamphlet) and the compound is a pharmaceutically acceptable salt.

  In another example, the compound is described in paragraph [0038] (of this international publication) and the compound is a prodrug.

  The present invention also provides Formula VI that modulates kinase activity, particularly Raf,

Or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein:
Each of R ⁵ and R ⁶ is —H, halogen, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _0-2 R ³ , —SO ₂ N ( _{^{R 3) R 3, -CO 2}} R 3, -C (O) N (R 3) R 3, -N (R 3) SO 2 R 3, -N (R 3) C (O) R 3, - N (R ³ ) CO ₂ R ³ , —C (O) R ³ , —OC (O) R ³ , optionally substituted C _1-6 alkyl, optionally substituted aryl, optionally substituted Independently selected from aryl C _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-6 alkyl;
n is 1 or 2 depending on the presence or absence of a saturated carbon bond between R ⁵ and R ⁶ ;
X ₁ , X ₂ and X ₃ are independently selected from —CR ¹ ═ or —N═;
Each of R ¹ is —H, halogen, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —SO ₂ N (R ³ ). R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R _{^{3) CO 2 R 3, -C}} (O) R 3, -OC (O) R 3, aryl aryl, optionally substituted substituted _{C 1 to 6} alkyl, optionally substituted optionally Independently selected from C _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-6 alkyl;
Z and ^{X, -C (R 2) =,} - N =, - N (R 2) -, - S (O) 0~2 -, and each independently selected from -O-;
E and Y are each independently selected from absent, —C (R ² ) (R ² ) —, —C (═O) —, —C (R ² ) ═ and —N═, Y is not both absent, and when both Z and X are -N =, E and Y are not both -N =;
Each of R ² is R ³ , —N (R ³ ) R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) CO ₂ R ³ , —N (R ³ ) C ( Independently selected from O) N (R ³ ) R ³ , and —N (R ³ ) C (O) R ³ ;
Each of R ³ is —H, optionally substituted C _1-6 alkyl, optionally substituted C _3-7 alicyclic, optionally substituted aryl, optionally substituted aryl Independently selected from C _1-3 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-3 alkyl;
Any two R ³ , when taken together with the common nitrogen to which they are attached, form an optionally substituted 5- to 7-membered heterocycle, said optionally substituted The 5- to 7-membered heterocycle optionally contains at least one additional heteroatom selected from N, O, S, and P;
G represents —CO ₂ R ³ , —C (O) R ³ , —C (O) N (R ³ ) R ³ , —C (O) (NR ³ ), —C (O) NR ³ [C ( R ³ ) ₂ ] _0-1 R ³ , —C (O) NR ³ O [C (R ³ ) ₂ ] _0-1 R ³ , —N (R ³ ) CO ₂ R ³ , —N (R ³ ) ^{C (O) N (R 3} ) R 3, -N (R 3) C (O) R 3, -N (R 3) R 3, -S (O) 0~2 R 3, -SO 2 N ( R ³ ) Selected from R ³ , optionally substituted aryl C _0-3 alkyl, and optionally substituted heterocyclic aryl C _0-3 alkyl.

In one example, the compound is described in paragraph [0055] (of this international pamphlet) and R ⁴ is —OH.

In one example, the compound is described in paragraph [0056] (of this International Publication Pamphlet), where G is —C (O) R ³ , —C (O) N (R ³ ) R ³ , —C (O) (NR ³ ), —C (O) NR ³ [C (R ³ ) ₂ ] _0-1 R ³ , —C (O) NR ³ O [C (R ³ ) ₂ ] _0-1 R ³ It is.

In one example, the compound is described in paragraph [0057] (of this International Publication Pamphlet) and G is —C (O) N (R ³ ) R ³ .

In one example, the compound is described in paragraph [0058] (of this International Publication) and G is —C (O) NHR ³ .

In one example, the compound is described in paragraph [0055] (of this International Publication Pamphlet) and R ³ is an optionally substituted C _1-6 alkyl.

In one example, the compound is described in paragraph [0055] (of this International Publication) and R ³ is optionally substituted aryl.

In one example, the compound is described in paragraph [0055] (of this International Publication Pamphlet) and R ³ is an optionally substituted aryl C _1-3 alkyl.

In one example, the compound is described in paragraph [0055] (of this International Publication Pamphlet) and R ³ is an optionally substituted heterocycle.

In one example, the compound is described in paragraph [0055] (of this International Publication Pamphlet) and R ³ is an optionally substituted heterocyclic C _1-3 alkyl.

In one example, the compound is described in paragraph [0055] (of this International Publication Pamphlet) and X ₁ , X ₂ and X ₃ are —CR ¹ ═.

  In one example, the compound is described in paragraph [0065] (of this International Publication Pamphlet) and E is absent.

In one example, the compound is described in paragraph [0066] (of this International Publication Pamphlet), Z is —N═; Y is —C (R ² ) ═; X is — N (R ² ) —, —S— and —O— are selected.

In one example, the compound is described in paragraph [0067] (of this International Publication Pamphlet) and R ⁵ and R ⁶ are optionally substituted C _1-6 alkyl.

  In one example, the compound is described in paragraph [0068] (of this International Publication Pamphlet) and m is 1.

  In one example, the compound is described in paragraph [0055] (of this international pamphlet) and the compound is a pharmaceutically acceptable salt.

  In one example, the compound is described in paragraph [0055] (of this international pamphlet) and the compound is a prodrug.

  The invention also provides Formula VII that modulates kinase activity, particularly Raf,

Or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, provided that the compound is not CAS Registry Number 439096-29-4, 439107-3-1, or 439107-34-3. In the formula
A is a 3- to 7-membered alicyclic, 5- to 6-membered ortho-arylene or 5- to 6-membered ortho-heteroarylene containing between 1 and 3 heteroatoms, Are optionally substituted by up to 4 R;
Each R, -H, _{^{halogen, -CN, -NO 2, -OR 3}} , -N (R 3) R 3, -S (O) 0~2 R 3, -SO 2 N (R 3) R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R ³⁾ ) CO ₂ R ³ , —C (O) R ³ , —OC (O) R ³ , optionally substituted C _1-6 alkyl, optionally substituted aryl, optionally substituted aryl C Independently selected from _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle _C1-6 alkyl;
Any two R, together with the atoms to which they are attached, form a first ring system fused with A, wherein the first ring system is substituted with 0 to 3 R ¹ There;
X ₁ , X ₂ and X ₃ are independently selected from —CR ¹ ═ or —N═;
Each of R ¹ is —H, halogen, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —SO ₂ N (R ³ ). R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R _{^{3) CO 2 R 3, -C}} (O) R 3, -OC (O) R 3, aryl aryl, optionally substituted substituted _{C 1 to 6} alkyl, optionally substituted optionally Independently selected from C _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-6 alkyl;
Z and ^{X, -C (R 2) =,} - N =, - N (R 2) -, - S (O) 0~2 -, and each independently selected from -O-;
E and Y are each independently selected from absent, —C (R ² ) (R ² ) —, —C (═O) —, —C (R ² ) ═ and —N═, Y cannot be both absent, and when both Z and X are -N =, E and Y are not both -N =;
Each of R ² is R ³ , —N (R ³ ) R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) CO ₂ R ³ , —N (R ³ ) C ( Independently selected from O) N (R ³ ) R ³ , and —N (R ³ ) C (O) R ³ ;
Each of R ³ is —H, optionally substituted C _1-6 alkyl, optionally substituted C _3-7 alicyclic, optionally substituted aryl, optionally substituted aryl Independently selected from C _1-3 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-3 alkyl;
Any two R ³ , when taken together with the common nitrogen to which they are attached, form an optionally substituted 5- to 7-membered heterocycle, said optionally substituted The 5- to 7-membered heterocycle optionally contains at least one additional heteroatom selected from N, O, S, and P; and R ⁴ is —H, —OH, optional It is selected from C _{1 to 6} alkoxy substituted in C _{1 to 6} alkyl and optionally substituted on.

  In one example, the compound is described in paragraph [0072] (of this International Publication) and A is a 6-membered ortho-arylene.

  In one example, the compound is described in paragraph [0073] (of this International Publication) and A is ortho-phenylene.

In one example, the compound is described in paragraph [0074] (of this International Publication Pamphlet) and R ⁴ is —OH.

In one example, the compound is described in paragraph [0072] (of this International Publication Pamphlet) and R ³ is an optionally substituted C _1-6 alkyl.

In one example, the compound is described in paragraph [0072] (of this International Publication) and R ³ is optionally substituted aryl.

In one example, the compound is described in paragraph [0072] (of this International Publication Pamphlet) and R ³ is an optionally substituted aryl C _1-3 alkyl.

In one example, the compound is described in paragraph [0072] (of this International Publication Pamphlet) and R ³ is an optionally substituted heterocycle.

In one example, the compound is described in paragraph [0072] (of this International Publication Pamphlet) and R ³ is an optionally substituted heterocyclic C _1-3 alkyl.

In one example, the compound is described in paragraph [0080] (of this International Publication Pamphlet) and X ₁ , X ₂ and X ₃ are —CR ¹ ═.

  In one example, the compound is described in paragraph [0081] (of this international pamphlet) and E is absent.

In one example, the compound is described in paragraph [0082] (of this International Publication Pamphlet), Z is —N═; Y is —C (R ² ) ═; X is — N (R ² ) —, —S—, and —O— are selected.

  In one example, the compound is described in paragraph [0072] (of this International Publication Pamphlet) and the compound is a pharmaceutically acceptable salt.

  In one example, the compound is described in paragraph [0072] (of this International Publication Pamphlet) and the compound is a prodrug.

  The present invention relates to Formula VIII that modulates kinase activity, particularly Raf,

Or a pharmaceutically acceptable salt, hydrate or prodrug thereof, provided that the compound is not CAS Registry Number 439096-29-4, 439107-3-1, or 439107-34-3 In the formula
A is a 5- to 6-membered ortho-arylene or a 5- to 6-membered ortho-heteroarylene containing between 1 and 3 heteroatoms, and any of the foregoing has up to 4 R Optionally substituted by:
Each R, -H, _{^{halogen, -CN, -NO 2, -OR 3}} , -N (R 3) R 3, -S (O) 0~2 R 3, -SO 2 N (R 3) R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R ³⁾ ) CO ₂ R ³ , —C (O) R ³ , —OC (O) R ³ , optionally substituted C _1-6 alkyl, optionally substituted aryl, optionally substituted aryl C Independently selected from _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle _C1-6 alkyl;
Any two R, together with the atoms to which they are attached, form a first ring system fused with A, wherein the first ring system is substituted with 0 to 3 R ¹ There;
n is 0 to 3;
Each of R ¹ is —H, halogen, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —SO ₂ N (R ³ ). R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R _{^{3) CO 2 R 3, -C}} (O) R 3, -OC (O) R 3, aryl aryl, optionally substituted substituted _{C 1 to 6} alkyl, optionally substituted optionally Independently selected from C _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-6 alkyl;
Z and ^{X, -C (R 2) =,} - N =, - N (R 2) -, - S (O) 0~2 -, and each independently selected from -O-;
E and Y are each independently selected from absent, —C (R ² ) (R ² ) —, —C (═O) —, —C (R ² ) ═ and —N═, Y is not both absent, and when both Z and X are -N =, E and Y are not both -N =;
Each of R ² is R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) CO ₂ R ³ , —N (R ³ ) C (O) N (R ³ ) R ³ , And —N (R ³ ) C (O) R ³ ;
Each R ^3, -H, heterocycle substituted C _{1 to 6} alkyl which is optionally substituted, aryl which is optionally substituted, aryl C _{1 to 3} alkyl which is optionally substituted, optionally And optionally selected from optionally substituted heterocycle C _1-3 alkyl;
Any two R ³ , when taken together with the common nitrogen to which they are attached, form an optionally substituted 5- to 7-membered heterocycle, said optionally substituted 5 The 7-membered heterocycle optionally contains at least one additional heteroatom selected from N, O, S, and P; and R ⁴ is —H, —OH, optionally substituted. Selected from C _1-6 alkyl and optionally substituted C _1-6 alkoxy.

  In one example, the compound is described in paragraph [0086] (of this international pamphlet) and E is absent.

  In another example, the compound is described in paragraph [0087] (of this International Publication) and A is ortho-phenylene.

  In another example, the formula IX described in paragraph [0088] (of this international pamphlet),

Wherein A, n, R, R ¹ , R ² , R ³ , R ⁴ , Z, Y, and X are as defined above.

In another example, the compound is described in paragraph [0082] (of this International Publication), Z is —N═; Y is —C (R ² ) ═; X is , —N (R ² ) —, —S—, and —O—.

In another example, the compound is described in paragraph [0090] (of this international pamphlet) and R and R ¹ are —H.

  In another example, the formula Xa or Xb described in paragraph [0091] (of this International Publication Pamphlet),

Wherein A, R ³ and R ⁴ are as defined above; R ² is —H or optionally substituted C _1-6 alkyl, and R ² is , -H, where all other groups are identical, of course, Xa and Xb represent single molecule tautomers; ^R3a represents -H or optionally substituted _{C1- 6} be either alkyl; R ^3b is substituted C _{1 to 6} alkyl which is optionally substituted, aryl which is optionally substituted, aryl C _{1 to 3} alkyl which is optionally substituted, optionally Selected from heterocyclic ring and optionally substituted heterocyclic C _1-3 alkyl.

In another example, the compound is described in paragraph [0092] (of this International Publication Pamphlet) and R ^3a is —H.

In another example, the compound is described in paragraph [0093] (of this international pamphlet) and R ² is —H.

In another example, the compound is described in paragraph [0094] (of this International Publication) and R ³ is optionally substituted aryl.

  In another example, the formula XI described in paragraph [0095] (of this international pamphlet),

Wherein R ³ is as defined above; R ^3b is optionally substituted C _1-6 alkyl, optionally substituted aryl, and optionally substituted. Selected from aryl C _1-3 alkyl.

In another example, the compound is described in paragraph [0096] (of this international pamphlet), wherein R ³ is a disubstituted aryl.

In another example, the compound is described in paragraph [0097] (of this international pamphlet), wherein R ³ is aryl disubstituted by alkyl and halogen.

  In another example, the compound is described in paragraph [0086] (of this international pamphlet) and the compound is a pharmaceutically acceptable salt.

  In another example, the compound is described in paragraph [0086] (of this international publication) and the compound is a prodrug.

  The present invention also provides Formula XII that modulates kinase activity, particularly Raf,

Or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein
Each of R ⁵ and R ⁶ is —H, halogen, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _0-2 R ³ , —SO ₂ N ( _{^{R 3) R 3, -CO 2}} R 3, -C (O) N (R 3) R 3, -N (R 3) SO 2 R 3, -N (R 3) C (O) R 3, - N (R ³ ) CO ₂ R ³ , —C (O) R ³ , —OC (O) R ³ , optionally substituted C _1-6 alkyl, optionally substituted aryl, optionally substituted Independently selected from aryl C _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-6 alkyl;
m is 1 or 2 depending on the presence or absence of a saturated carbon bond between R ⁵ and R ⁶ ;
X ₁ , X ₂ and X ₃ are independently selected from —CR ¹ ═ or —N═;
Each of R ¹ is —H, halogen, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —SO ₂ N (R ³ ). R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R _{^{3) CO 2 R 3, -C}} (O) R 3, -OC (O) R 3, aryl aryl, optionally substituted substituted _{C 1 to 6} alkyl, optionally substituted optionally Independently selected from C _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-6 alkyl;
Z and ^{X, -C (R 2) =,} - N =, - N (R 2) -, - S (O) 0~2 -, and each independently selected from -O-;
E and Y are each independently selected from absent, —C (R ² ) (R ² ) —, —C (═O) —, —C (R ² ) ═ and —N═, Y is not both absent, and when both Z and X are -N =, E and Y are not both -N =;
Each of R ² is R ³ , —N (R ³ ) R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) CO ₂ R ³ , —N (R ³ ) C ( Independently selected from O) N (R ³ ) R ³ , and —N (R ³ ) C (O) R ³ ;
Each of R ³ is —H, optionally substituted C _1-6 alkyl, optionally substituted C _3-7 alicyclic, optionally substituted aryl, optionally substituted aryl Independently selected from C _1-3 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-3 alkyl;
Any two R ³ , when taken together with the common nitrogen to which they are attached, form an optionally substituted 5- to 7-membered heterocycle, said optionally substituted The 5- to 7-membered heterocycle optionally contains at least one additional heteroatom selected from N, O, S, and P;
R ⁴ is selected from —H, —OH, optionally substituted C _1-6 alkyl and optionally substituted C _1-6 alkoxy.

In one example, the compound is described in paragraph [00101] (of this International Publication Pamphlet) and R ⁴ is —OH.

In one example, the compound is described in paragraph [00101] (of this International Publication Pamphlet), where G is —C (O) R ³ , —C (O) N (R ³ ) R ³ , —C (O) (NR ³ ), —C (O) NR ³ [C (R ³ ) ₂ ] _{0 to 1} R ³ , —C (O) NR ³ O [C (R ³ ) ₂ ] _{0 to 1} R ³ It is.

In one example, the compound is described in paragraph [00103] (of this International Publication Pamphlet) and G is —C (O) N (R ³ ) R ³ .

In one example, the compound is described in paragraph [00104] (of this International Publication Pamphlet) and G is —C (O) NHR ³ .

In one example, the compound is described in paragraph [00101] (of this International Publication Pamphlet) and R ³ is an optionally substituted C _1-6 alkyl.

In one example, the compound is described in paragraph [00101] (of this international pamphlet) and R ³ is an optionally substituted aryl.

In one example, the compound is described in paragraph [00101] (of this International Publication Pamphlet), where R ³ is an optionally substituted aryl C _1-3 alkyl.

In one example, the compound is described in paragraph [00101] (of this international pamphlet) and R ³ is an optionally substituted heterocycle.

In one example, the compound is described in paragraph [00101] (of this International Publication Pamphlet) and R ³ is an optionally substituted heterocyclic C _1-3 alkyl.

In one example, the compound is described in paragraph [00101] (of this International Publication Pamphlet) and X ₁ , X ₂ and X ₃ are —CR ¹ ═.

  In one example, the compound is described in paragraph [00111] (of this International Publication) and E is absent.

In one example, the compound is described in paragraph [00112] (of this International Publication Pamphlet), Z is —N═; Y is —C (R ² ) ═; and X is Selected from —N (R ² ) —, —S—, and —O—.

In one example, the compound is described in paragraph [00113] (of this International Publication Pamphlet) and R ⁵ and R ⁶ are optionally substituted C _1-6 alkyl.

  In one example, the compound is described in paragraph [00114] (of this International Publication Pamphlet) and m is 1.

  In one example, the compound is described in paragraph [00101] (of this international pamphlet) and the compound is a pharmaceutically acceptable salt.

  In one example, the compound is described in paragraph [00101] (of this international pamphlet) and the compound is a prodrug.

  The present invention also provides Formula XIII that modulates kinase activity, particularly Raf.

Or a pharmaceutically acceptable salt, hydrate or prodrug thereof, but said compound is not CAS Registry Number 439096-29-4, 439107-32-1, or 439107-34-3 In conditions;
A is a 5- to 6-membered ortho-arylene or a 5- to 6-membered ortho-heteroarylene containing between 1 and 3 heteroatoms, and any of the foregoing is 4 Optionally substituted with up to two R;
Each R, -H, _{^{halogen, -CN, -NO 2, -OR 3}} , -N (R 3) R 3, -S (O) 0~2 R 3, -SO 2 N (R 3) R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R ³⁾ ) CO ₂ R ³ , —C (O) R ³ , —OC (O) R ³ , optionally substituted C _1-6 alkyl, optionally substituted aryl, optionally substituted aryl C Independently selected from _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle _C1-6 alkyl;
Any two R, together with the atoms to which they are attached, form a first ring system fused with A, wherein the first ring system is substituted with 0 to 3 R ¹ There;
Each of R ¹ is —H, halogen, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —SO ₂ N (R ³ ). R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R _{^{3) CO 2 R 3, -C}} (O) R 3, -OC (O) R 3, aryl aryl, optionally substituted substituted _{C 1 to 6} alkyl, optionally substituted optionally Independently selected from C _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-6 alkyl;
Each R ^3, -H, heterocycle substituted C _{1 to 6} alkyl which is optionally substituted, aryl which is optionally substituted, aryl C _{1 to 3} alkyl which is optionally substituted, optionally And optionally selected from optionally substituted heterocycle C _1-3 alkyl;
Any two R ³ , when taken together with the common nitrogen to which they are attached, form an optionally substituted 5- to 7-membered heterocycle, said optionally substituted The 5- to 7-membered heterocycle optionally contains at least one additional heteroatom selected from N, O, S, and P;
R ⁴ is selected from —H, —OH, optionally substituted C _1-6 alkyl and optionally substituted C _1-6 alkoxy.

  In another example, the compound is described in paragraph [00118] (of this International Publication) and A is ortho-phenylene.

In another example, the compound is described in paragraph [00119] (of this International Publication) and R ⁴ is —OH.

In another example, the compound is described in paragraph [00120] (of this International Publication) and R ³ is an optionally substituted aryl.

In another example, the compound is described in paragraph [00121] (of this international pamphlet), and R ³ is an optionally substituted mono- or di-substituted phenyl.

In another example, the compound is described in paragraph [00120] (of this International Publication) and R ³ is an optionally substituted aryl C _1-3 alkyl.

In another example, the compound is described in paragraph [00120] (of this International Publication) and R ³ is an optionally substituted heterocycle.

In another example, the compound is described in paragraph [00120] (of this International Publication) and R ³ is an optionally substituted heterocycle C _1-3 alkyl.

  In one example, the compound is described in paragraph [00118] (of this International Publication Pamphlet) and the compound is a pharmaceutically acceptable salt.

  In one example, the compound is described in paragraph [00118] (of this International Publication Pamphlet) and the compound is a prodrug.

  In another example, the compound is described in any one of paragraphs [0020]-[00127] (of this International Publication) selected from Table 1 or Table 2 below.

  Another aspect of the present invention comprises a compound described in any one of paragraphs [0020]-[00128] (of this International Publication Pamphlet) and at least one pharmaceutically acceptable carrier or excipient. Is a pharmaceutical composition.

  Another aspect of the present invention is a metabolite of the compound or pharmaceutical composition described in any one of paragraphs [0020] to [00129] (of this International Publication Pamphlet).

  Another aspect of the present invention is a method of modulating the in vivo activity of a kinase, the method comprising at least one compound according to any of paragraphs [0020] to [00128] (of this international publication) And a pharmaceutical composition according to paragraph [00129] (of this International Publication Pamphlet) and compounds of CAS Registry Number 439096-29-4, 439107-32-1, or 439107-34-3 and them Administering to a subject an effective amount of the pharmaceutical composition.

  Another embodiment of the present invention is the method according to paragraph [00131] (of this international pamphlet), wherein the kinase is Raf.

  Another aspect of the invention is the method of paragraph [00132] (of this International Publication), wherein modulation of Raf's in vivo activity comprises inhibition of Raf.

  Another aspect of the present invention is a method of treating a disease or disorder associated with uncontrolled, abnormal and / or undesirable cellular activity, the method comprising paragraph [0020] (of this International Publication). ] To a composition comprising at least one compound according to any one of [00128] and a pharmaceutical composition according to paragraph [00129] (of this International Publication Pamphlet), and CAS Registry Number 439096-29-4 Administering to a subject in need thereof a therapeutically effective amount of a compound of 439107-32-1 or 439107-34-3 and pharmaceutical compositions thereof.

  Another aspect of the present invention is a method for screening for a modulator of Raf kinase, the method comprising at least one compound according to any of paragraphs [0020] to [00128] (of this International Publication). And the pharmaceutical composition of paragraph [00129] (of this International Publication Pamphlet), or the compound of CAS Registry Number 439096-29-4, 439107-32-1, or 439107-34-3 and Combining any of those pharmaceutical compositions, as well as at least one candidate agent, and determining the effect of the candidate agent on the activity of the kinase.

  Another aspect of the present invention is a method for inhibiting the proliferation activity in a single cell or a plurality of cells, the method comprising any one of paragraphs [0020] to [00128] (of this international pamphlet). And at least one compound described in paragraph [00129] (of this International Publication Pamphlet), or CAS registration number 439096-29-4, 439107-3-1, or 439107-34-3 Administering an effective amount of the compounds and pharmaceutical compositions thereof to the cell or cells.

  Another aspect of the present invention is a method for preparing a compound according to any of paragraphs [0020] to [00129] (of this International Publication Pamphlet).

(Definition)
As used herein, the following words and idioms have the following meanings, except to the extent that the context in which they are used is otherwise specified, or to the extent that they are specifically defined to mean something different: It is generally intended to have

  The symbol “-” means a single bond, “=” means a double bond, and “≡” means a triple bond. symbol

Refers to the group on the double bond occupying any position at the end of the double bond with the symbol; that is, the geometry of the double bond, E- and Z-, is ambiguous . If a group is drawn away from its parent expression, the symbol

Is used at the bond end that is theoretically cleaved to separate the group from its parent structure.

A chemical formula is accompanied by a list of formulas or verbages that describe the scope of what is meant by the descriptor using a descriptor such as “R ¹ ”. Descriptors such subsequent "R ^1a" is used to describe some of the subset of the range of R ^1, "R ^1b" is written and another subset of the range of R ¹ Used to do so, etc. In such a continuation, all other formulas containing simply “R ¹ ” are meant to include the full range of the descriptor.

When a chemical structure is depicted or described, it is assumed that all carbons have a hydrogen substitution compatible with tetravalent unless otherwise stated. For example, nine hydrogens are implied in the structure on the left side of the following figure. Nine hydrogens are depicted in the structure on the right. Sometimes a particular atom in the structure is described as having a substituted hydrogen in the formula in the text (particularly defined hydrogen), for example, —CH ₂ CH ₂ —. It is understood by those of ordinary skill in the art that the above described notation is common in chemical technology to provide simplicity and simplicity for the description of other complex structures.

In the present application, several ring structures are comprehensively depicted and described herein. For example, in the structure on the left side of the figure below, when ring A is used to represent a “spiro ring”, and thus when ring A is cyclopropyl, at most 4 hydrogens (“R” is also − H can be on H). In another example, as depicted on the right side of the figure below, when ring B is used to represent “phenylene”, there can be at most 4 hydrogens on ring B (the depicted cleavage bond Is not a C—H bond).

For example, the formula:

Where the group “R” is depicted as being “floating” on the ring system, the substituent “R” can be present on any atom of the ring system and is stable unless otherwise defined. As long as such a structure is formed, it is envisaged that a hydrogen depicted, implied or specifically defined from one of the ring atoms has been replaced.

  The group “R” can be represented, for example, by the formula:

When depicted as floating on a fused ring system of
Unless otherwise defined, the substituent “R” may be present on any atom of the fused ring system and, as long as a stable structure is formed, hydrogen depicted from one of the ring atoms (eg, — NH-), implied hydrogen (eg, as in the above formula that does not show hydrogen but is understood to be present), or specifically defined hydrogen (eg, “X” in the above formula is ═CH— Is assumed to have been replaced. In the depicted example, the “R” group can be present on either the 5-membered ring or the 6-membered ring of the fused ring system. In the formula depicted above, for example, when y is 2, two “R” s may be present on any two atoms of the ring system, each also depicted on the ring, or implied. It is assumed that it has been replaced with hydrogen that has been made or specifically defined.

  The group “R” can be represented, for example, by the formula:

Is depicted as being present on a ring system containing saturated carbon,
In this example, in this example, “y”, each of which is actually drawn on the ring, implied or assumed to be substituted with a specifically defined hydrogen, can be one or more; but is not defined separately As long as the resulting structure is stable, the two “R” s can be on the same carbon. A simple example is when R is a methyl group; there can be a twin dimethyl on the depicted ring carbon ("cyclic" carbon). In another example, two Rs on the same carbon can include that carbon to form a ring, thus, for example, the formula:

Creates a spiro ring ("spiro ring" group) structure having the ring depicted in.

“Alkyl” is intended to include generically linear, branched, or cyclic hydrocarbon structures, and combinations thereof. For example, “C ₈ alkyl” may refer to n-octyl, iso-octyl, cyclohexylethyl, and the like. Lower alkyl refers to an alkyl group of 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and the like. Higher alkyl refers to an alkyl group containing more than 8 carbon atoms. Representative alkyl groups are those of C ₂₀ or less. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3 to 13 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like. In this application, alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thus, when an alkyl residue having a certain number of carbons is named, it is intended to encompass all geometric isomers having that number of carbons; thus, for example, “butyl” or “C “ ₄ alkyl” is meant to include n-butyl, s-butyl, isobutyl, t-butyl, isobutenyl and but-2-yne groups; for example, “propyl” or “C ₃ Each of “alkyl” includes n-propyl, propenyl and isopropyl. Alternatively, if the alkenyl and / or alkynyl descriptor is used in the specific definition of “C ₄ alkenyl” together with a group, eg, “C ₄ alkyl”, then the C ₄ alkenyl geometric isomer is referred to as “C ₄ alkyl”. Although not meant to be included, another 4-carbon isomer is, for example, C ₄ alkynyl. For example, a more general description, intended to encompass the present invention as a whole, may describe a particular group as “C _1-8 alkyl”, while preferred species may refer to the same group as “ It can be described as “C _1-8 alkyl”, “C _1-6 alkenyl”, “C _1-5 alkynyl” and the like.

“Alkylene” refers to a straight or branched divalent group consisting of only carbon and hydrogen atoms, containing no unsaturation and having from 1 to 10 carbon atoms, such as methylene , Ethylene, propylene, n-butylene and the like. Alkylene is a subset of alkyl and refers to the same residues as alkyl, but has two points of attachment and is specifically fully saturated. Examples of alkylene include ethylene (—CH ₂ CH ₂ —), propylene (—CH ₂ CH ₂ CH ₂ —), dimethyl propylene (—CH ₂ C (CH ₃ ) ₂ CH ₂ —), and cyclohexyl propylene (— _{CH 2 CH 2 CH (C 6} H 13)). Is mentioned.

  “Alkylidene” means a linear or branched unsaturated divalent group consisting of only carbon and hydrogen atoms having 2 to 10 carbon atoms, such as ethylidene, propylidene, n- This refers to butylidene. Alkylidene is a subset of alkyl and refers to the same residues as alkyl but has two points of attachment, and in particular double bond unsaturation. The unsaturation present includes at least one double bond.

  “Alkylidin” means a linear or branched unsaturated divalent group consisting of only carbon and hydrogen atoms having 2 to 10 carbon atoms, for example, propyl-2-ynyl, n-butylide-1-ynyl and the like. Alkylidene is a subset of alkyl and refers to the same residues as alkyl but has two points of attachment, and in particular triple bond unsaturation. The unsaturation present includes at least one triple bond.

  When any of the above groups, “alkylene”, “alkylidene” and “alkylidine” are optionally substituted, they can themselves contain an alkyl substitution containing unsaturation. For example, 2- (2-phenylethynyl-but-3-enyl) -naphthalene (IUPAC nomenclature) contains an n-butylid-3-ynyl group having a vinyl substituent at the 2-position of the group.

  “Alkoxy” or “alkoxyl” refers to an —O-alkyl group, for example, a straight chain, branched chain of 1 to 8 carbon atoms attached to the parent structure through an oxygen atom, Includes cyclic structures, unsaturated chains, and combinations thereof. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower alkoxy refers to a group containing 1 to 6 carbons.

“Substituted alkoxy” refers to the group —O- (substituted alkyl), where substitution on the alkyl group generally includes something other than carbon only (as defined by alkoxy). One representative substituted alkoxy group is “polyalkoxy” or —O— (optionally substituted alkylene)-(optionally substituted alkoxy), such as —OCH ₂ CH ₂ OCH ₃ and polyethylene glycol and —O Glycol ethers such as (CH ₂ CH ₂ O) _x CH ₃ , where x is an integer between about 2 and about 20, in another example an integer between about 2 and about 10, further In the example, it is an integer between about 2 and about 5. Another representative substituted alkoxy group is hydroxyalkoxy or —OCH ₂ (CH ₂ ) _y OH, where y is, for example, an integer between about 1 and about 10, in another example y is An integer between about 1 and about 4.

  “Acyl” refers to straight, branched, cyclic, saturated and unsaturated aromatics of 1 to 10 carbon atoms attached to the parent structure through a carbonyl function, and Refers to the combination of One or more carbons in the acyl residue can be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent is carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl refers to a group containing 1 to 6 carbons.

  “Α-amino acids” refers to natural and commercially available amino acids and optical isomers thereof. Typical natural and commercially available α-amino acids are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine, arginine, cysteine , Homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. “The side chain of an α-amino acid” refers to a group found on the α-carbon of an α-amino acid as defined above, such as hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), and the like. .

“Amino” refers to the group —NH ₂ . “Substituted amino” refers to the group —N (H) R or —N (R) R, wherein each R is a group: optionally substituted alkyl, optionally substituted alkoxy, Independently substituted aryl, optionally substituted heterocycle, acyl, carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example, dimethylamino, methylsulfonylamino, and furanyl-oxy -Sulfonamino.

  “Aryl” refers to a monovalent group such as an aromatic 6- to 14-membered carbocyclic ring, such as benzene, naphthalene, indane, tetralin, fluorene, and the like. As monovalent groups, the foregoing ring examples are named phenyl, naphthyl, indanyl, tetralinyl, and fluorenyl.

  “Arylene” generally refers to any aryl having at least two non-hydrogen groups attached thereto. For a more specific example, “phenylene” refers to a divalent phenyl ring group. Thus, phenylene can have more than one linking group, but is defined by a minimum of two non-hydrogen groups attached to it. The terms “ortho-arylene”, “meta-arylene”, “para-arylene” refer to the geometric isomers of a particular arylene, and the two groups attached to the aryl depicted in the formula are each ortho to the aryl. Placed in the geometrical relationship of meta or para.

“Arylalkyl” refers to a residue in which an aryl moiety is attached to the parent structure via one of an alkylene, alkylidene, or alkylidyne group. Examples include benzyl, phenethyl, phenyl vinyl, phenyl allyl and the like. Both the aryl group portion of the arylalkyl group and the corresponding alkylene group portion, alkylidene group portion, or alkylidine group portion can be optionally substituted. “Lower arylalkyl” refers to an arylalkyl in which the “alkyl” portion of the group has 1 to 6 carbons; this can also be referred to as an _{arylC 1-6} alkyl.

  “Exo-alkenyl” refers to a double bond protruding from a cyclic carbon and not within the ring system, eg, a double bond depicted in the formula below.

In some instances, as will be recognized by one of ordinary skill in the art, two adjacent groups of the aromatic system can be fused together to form a ring structure. The fused ring structure can contain heteroatoms and can be optionally substituted with one or more groups. Furthermore, it should be noted that the saturated carbon (ie, saturated ring structure) of such fused groups can contain two substituents.

  “Fused polycyclic” or “fused ring system” refers to a polycyclic ring system containing a bridged ring or fused ring; that is, two rings have more than one share in their ring structure Has atoms. In this application, a fused polycyclic or fused ring system is not necessarily all an aromatic ring system. Typically, though not necessarily, fused polycyclics share a contiguous set of atoms, such as naphthalene or 1,2,3,4-tetrahydro-naphthalene. Spiro ring systems are not fused rings according to this definition, but the fused polycyclic systems of the present invention can themselves have a spiro ring attached to it via a fused polycyclic single ring atom.

  “Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine. “Haloalkyl” and “haloaryl” generally refer to alkyl and aryl groups that are each substituted with one or more halogens. Thus, “dihaloaryl”, “dihaloalkyl”, “trihaloaryl” and the like refer to aryl and alkyl substituted by multiple halogens, but not necessarily the same multiple halogens; thus, 4-chloro-3- Fluorophenyl is within the scope of dihaloaryl.

  “Heteroarylene” generally refers to any heteroaryl having at least two groups attached thereto. For a more specific example, “pyridylene” refers to a divalent pyridyl ring group. Thus, a pyridylene can have more than one group attached, but is defined by a minimum of two non-hydrogen groups attached to it. For the purposes of this application, the term “ortho-heteroarylene” refers to the geometric isomerism of a particular heteroarylene in which the two groups attached to the heteroaryl depicted in the formula are located on adjacent atoms of the heteroaryl. Refers to the body.

“Hetero atom” refers to O, S, N, or P “Heterocycle” means carbon atom and 1 to 5 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur A stable 3-membered ring group to a 15-membered ring group consisting of For purposes of this invention, a heterocyclic group can be a monocyclic, bicyclic or tricyclic ring system that can include fused or bridged ring systems as well as spiro ring systems; The nitrogen atom, phosphorus atom, carbon atom or sulfur atom can be optionally oxidized to various oxidation states. In specific examples, the —S (O) _0-2- group refers to —S— (sulfide), —S (O) — (sulfoxide), and —SO ₂ — (sulfone). For convenience, nitrogen, particularly but not exclusively defined as cyclic aromatic nitrogen, is meant to include their corresponding N-oxides, but is clearly defined as such in certain examples. Not. Thus, for example, for a compound of the invention having a pyridyl ring; the corresponding pyridyl-N-oxide is meant to be included as another compound of the invention. Furthermore, the cyclic nitrogen atom can optionally be quaternized; the ring group can be partially or fully saturated or aromatic. Examples of heterocyclic groups include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, Phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- Oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydride Pyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl Isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieri Yl, thiamorpholinyl, thiamorpholinylsulfoxy , Thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl and the like.

  “Heteroalicyclic” refers specifically to a non-aromatic heterocyclic group. Heteroalicyclics can contain unsaturation but are not aromatic.

  “Heteroaryl” refers specifically to an aromatic heterocyclic group.

“Heterocyclic alkyl” refers to a residue in which a heterocycle is attached to the parent structure through one of an alkylene, alkylidene, or alkylidyne group. Examples include (4-methylpiperazin-1-yl) methyl, (morpholin-4-yl) methyl, (pyridin-4-yl) methyl, 2- (oxazolin-2-yl) ethyl, 4- (4- Methylpiperazin-1-yl) -2-butenyl and the like. Both the heterocyclic group moiety of the heterocyclic alkyl group and the corresponding alkylene group, alkylidene group moiety or alkylidine group moiety can be optionally substituted. “Lower heterocyclic alkyl” refers to a heterocyclic alkyl wherein the “alkyl” portion of the group has 1 to 6 carbons. “Heteroalicyclic alkyl” refers to a heterocyclealkyl in which the “heterocycle” portion of the group is non-aromatic, especially; “heteroarylalkyl” refers to the “heterocycle” portion of the group, Heterocyclic alkyl that is aromatic is specifically named. Such terms can be described in one or more ways, for example, “lower heterocycle alkyl” and “heterocycle C _1-6 alkyl” are equivalent terms.

“Any” or “arbitrary” may or may not occur for an event or situation described thereafter, and this description does not cause that event or situation if it occurs Means to include cases. One of ordinary skill in the art will understand that for any molecule described as containing one or more optional substituents, only sterically practical compounds and / or compounds capable of synthesis can be included. I will. “Optionally substituted” refers to all subsequent modifiers in the term, eg, in the term “optionally substituted aryl C _1-8 alkyl”, optional substitution refers to the molecule's Can occur in both a “C _1-8 alkyl” moiety and an “aryl” moiety; for example, an optionally substituted alkyl includes an optionally substituted cycloalkyl group, which is then optionally substituted Defined as containing an infinite number of possible alkyl groups. A list of representative optional substitutions is included in the definition of “substituted” below.

  “Saturated bridged ring system” refers to a bicyclic or polycyclic ring system that is not aromatic. Such systems can contain isolated or conjugated unsaturation, but are not aromatic or heteroaromatic in their core structure (but may have aromatic substitution in their core structure). For example, hexahydro-furo [3,2-b] furan, 2,3,3a, 4,7,7a-hexahydro-1H-indene, 7-aza-bicyclo [2.2.1] heptane, and 1,2 , 3,4,4a, 5,8,8a-Octahydro-naphthalene are all included in the class of “saturated bridged ring systems”.

  A “spiro ring” or “spiro cyclic ring” refers to a ring derived from a particular cyclic carbon of another ring. For example, as depicted below, a ring atom of a saturated bridged ring system that is not a bridgehead atom (B and B ′ rings) is between the saturated bridged ring system and the spiro ring (A ring) attached to it. Can be a shared atom. Spiro rings can be carbocyclic or heteroalicyclic.

“Substituted” alkyl, aryl, and heterocycle are alkyls in which one or more (eg, up to about 5, in another example, up to about 3) hydrogen atoms: optionally substituted (eg, , Fluoromethyl, hydroxypropyl, nitromethyl, aminoethyl, etc.), optionally substituted aryl (eg 4-hydroxyphenyl, 2,3-difluorophenyl etc.), optionally substituted arylalkyl (eg 1 -Phenyl-ethyl, para-methoxyphenylethyl, etc.), optionally substituted heterocycle alkyl (eg 1-pyridin-3-yl-ethyl, N-ethylmorpholino, etc.), optionally substituted heterocycle (Eg, 5-chloro-pyridin-3-yl, 1-methyl-piperidin-4-yl, etc.), optionally substituted Alkoxy (eg, methoxyethoxy, hydroxypropyloxy, methylenedioxy, etc.), optionally substituted amino (eg, methylamino, diethylamino, trifluoroacetylamino, etc.), optionally substituted amidino, optionally Substituted aryloxy (eg phenoxy, para-chlorophenoxy, meta-aminophenoxy, para-phenoxyphenoxy, etc.), optionally substituted arylalkyloxy (eg benzyloxy, 3-chlorobenzyloxy, meta -Phenoxybenzyloxy, etc.), carboxy (—CO ₂ H), optionally substituted carboalkoxy (ie acyloxy or —OC (═O) R), optionally substituted carboxyalkyl (ie esters) Or —CO ₂ R), optionally substituted carboxamide, optionally substituted benzyloxycarbonylamino (CBZ-amino), cyano, optionally substituted acyl, halogen, hydroxy, nitro, optionally substituted Alkylsulfanyl, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, thiol, oxo, carbamyl, optionally substituted acylamino, optionally substituted hydrazino, and optionally substituted Refers to alkyl, aryl, and heterocycle, each substituted with a substituent independently selected from hydroxyamino, optionally substituted sulfonamido.

  “Sulfanyl” refers to the group —S— (optionally substituted alkyl), —S— (optionally substituted aryl) and —S— (optionally substituted heterocycle). .

  “Sulfinyl” refers to the group —S (O) —H, —S (O) — (optionally substituted alkyl), —S (O) — (optionally substituted aryl), and — Refers to an S (O)-(optionally substituted heterocycle) group.

“Sulfonyl” means: —S (O ₂ ) —H group, —S (O ₂ ) — (optionally substituted alkyl) group, —S (O ₂ ) — (optionally substituted aryl) groups, -S _(O 2) - group (heterocyclic optionally substituted), -S _(O 2) - (optionally substituted by are alkoxy) group, -S _(O 2) - (optionally substituted has been and aryloxy) group, and -S (O 2) _- (referred to heterocyclic oxy) group which is optionally substituted.

  The “yield” for each reaction described herein is expressed as a percentage of the theoretical yield.

  Some of the compounds of the present invention may have imino substituents, amino substituents, oxo substituents or hydroxy substituents that are remote from the aromatic heterocyclic ring system. For the purposes of this disclosure, such imino substituents, amino substituents, oxo substituents or hydroxy substituents may exist in their corresponding tautomers, ie amino, imino, hydroxy or oxo, respectively. Is solved.

  The compounds of the invention are named according to the systematic application of the nomenclature agreed by the International Pure and Applied Chemistry Association (IUPAC), International Biochemistry and Molecular Biology Association (IUBMB) and Chemical Abstract Service (CAS). The compounds were named using the naming authority published by the ACD / Labs-ACD / Nomenclature Batch 7.00 Release, Product 7.10 Edition, Toronto, Canada, September 15, 2003, Toronto, Canada.

  The compounds of the invention, or their pharmaceutically acceptable salts, can have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure.

  The compounds of the invention and their pharmaceutically acceptable salts can exist as single stereoisomers, racemates, and enantiomeric and diastereomeric mixtures. The compounds can also exist as geometric isomers. All such single stereoisomers, racemates, and mixtures and geometric isomers thereof are intended to be within the scope of the present invention.

  In view of the general description of the compounds of the present invention for the purpose of constructing compounds, it is assumed that such construction results in the creation of stable structures. That is, one skilled in the art will recognize that there may be several theoretical constructs that would not normally be considered as stable compounds (ie, the steric utility and / or synthetic feasibility described above). Will.

Where a particular group having that binding structure is shown as bound to two partners; that is, a divalent group, eg, —OCH ₂ —, unless otherwise stated, It is understood that either can be attached to a particular group at one end and the other partner will necessarily be attached to the other end of the particular group. In other words, divalent groups should not be construed as limited to the depicted direction, for example, “—OCH ₂ —” includes not only the depicted “—OCH ₂ —”, It also means “—CH ₂ O—”.

  Methods for the preparation and / or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)-and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional methods. Enantiomers (R- and S-isomers) are formed by diastereomeric salts or complexes that can be separated by methods known to those of ordinary skill in the art, for example by crystallization; for example, crystallization, enantiomers By the selective reaction of one enantiomer with a body-specific reagent, for example through the formation of diastereomeric derivatives that can be separated by enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or chiral Resolution can be achieved by gas-liquid or liquid chromatography on the environment, for example on a chiral support such as silica bound with a chiral ligand, or in the presence of a chiral solvent. It will be appreciated that the desired enantiomer is converted to another chemical moiety by one of the separation methods described above, but additional steps are required to liberate the desired enantiomer. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting enantiomers to others by asymmetric transformations. For a mixture of enantiomers enriched in a particular enantiomer, the main component enantiomer can be further enriched by recrystallization (due to a reduction in the yield of concomitant).

  “Patient” for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus, the method is applicable to both human therapy and veterinary applications. In a preferred embodiment, the patient is a mammal and in the most preferred embodiment the patient is a human.

  “Kinase-dependent diseases or conditions” refer to pathological conditions that depend on the activity of one or more protein kinases. Kinases are involved in signal transduction pathways of various cellular activities, directly or indirectly, such as proliferation, adhesion, migration, differentiation and invasion. Diseases associated with kinase activity include tumor growth, pathological neovascularization that supports solid tumor growth, and excessive local angiogenesis is associated with ocular diseases (such as diabetic retinopathy, age-related macular degeneration) and inflammation (psoriasis). And other diseases including rheumatoid arthritis).

  While not wishing to be bound by theory, phosphatases can also play a role in “kinase-dependent diseases or conditions” as a family of kinases; ie, kinases phosphorylate protein substrates and phosphatases Dephosphorylate. Accordingly, the compounds of the present invention can also directly or indirectly modulate phosphatase activity while modulating kinase activity as described herein. Where this additional modulation is present, it can be synergistic (or non-synergistic) to the activity of the compounds of the invention relative to an associated or otherwise dependent kinase or kinase family. In any of the cases described above, the compounds of the present invention reduce abnormal levels of angiogenesis associated with cell proliferation (ie, tumor growth), programmed cell death (apoptosis), cell migration and invasion and tumor growth. Useful for treating partially characterized diseases.

  A “therapeutically effective amount” is the amount of a compound of the invention that ameliorates the symptoms of the disease when administered to a patient. The amount of a compound of the invention that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient being treated, and the like. A therapeutically effective amount can be routinely determined by one of ordinary skill in the art in light of his or her knowledge and this disclosure.

“Cancer” refers to, but not limited to, the following cell proliferative disease states: heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma Lung : Bronchiogenic carcinoma (squamous epithelium, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) cancer, bronchial adenocarcinoma, sarcoma, lymphoma, chondromatoid Hanlatoma, Inesothelioma; gastrointestinal : esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (glandular carcinoma, insulinoma), Glucagonoma, gastrinoma, carcinoma, bipoma), small intestine (adenocarcinoma, lymphoma, carcinoma), Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, adenoma), large intestine (gland) , Tubular adenoma, chorionic adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms tumor [neplrroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional epithelium) Cancer, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicles (spermatoblastoma, teratomas, embryonic cancer, teratocarcinoma, choriocarcinoma, sarcoma, intercellular carcinoma, fibroma, fibroadenoma, adenoid tumor, fat Liver ): liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, hemangiosarcoma, hepatocellular adenoma, hemangioma; bone : osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, Chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, cartilage mucus fibroma, osteoid osteoma and giant cell tumors; Through system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, glioma disease), brain (Hoshijoshu, medulloblastoma, Glioma, ventricular ependymoma, germinocytoma [pineoblastoma], glioblastoma multiforme, oligodendroglioma, Schwann celloma, retinoblastoma, congenital tumor), spinal neurofibroma, marrow Gynecology : uterus (uterine body cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer [serious cystadenocarcinoma, mucinous cyst gland) Cancer, unclassified cancer], granulosa encapsulated tumor, Sertoli Leich cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma) , Vaginal (clear cell carcinoma, squamous cell carcinoma, grape sarcoma (fetal rhabdomyosarcoma), oviduct (cancer); hematology : blood (myeloid leukemia [acute and chronic], acute lymphacute leukemia, Chronic lymphatic acute leukemia, myeloproliferative disorder, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; skin : malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Morse Dysplastic nevi, lipoma, hemangioma, dermal fibroma, keloid, psoriasis; and adrenal gland : neuroblastoma. Accordingly, the term “cancerous cell” provided herein includes cells affected by any one of the above identified pathologies.

  “Pharmaceutically acceptable acid addition salts” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, as well as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, Formed with organic acids such as maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, transdermal acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid Refers to salts that retain the biological effectiveness of the free base and are not biologically or otherwise undesirable.

  “Pharmaceutically acceptable base addition salts” include sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and other inorganic bases. What is induced. Typical salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines such as naturally substituted amines, cyclic amines, and basics. Ion exchange resins (eg, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, And salts of glucosamine, methylglucamine, theobilomine, purines, piperazine, piperidine, N-ethylpiperidine, and poramine resin). Typical organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, eg, SM Berge et al., “Pharmaceutical Salts” J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

  “Prodrug” refers to a compound that is transformed (typically rapidly) in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. General examples include, but are not limited to, ester forms and amide forms of compounds having an active form having a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the present invention include, but are not limited to, alkyl esters in which the alkyl group is straight or branched (eg, having between about 1 and about 6 carbons). Have). Acceptable esters also include, but are not limited to, cycloalkyl esters and arylalkyl esters such as benzyl. Examples of pharmaceutically acceptable amides of the compounds of the present invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (eg, between about 1 and about 6). Of carbon). Amides and esters of the compounds of the present invention can be prepared by conventional methods. A thorough discussion of prodrugs can be found in T.W. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems”, A.M. C. S. Symposium Series Vol 14, and Bioreversible Carriers in Drug Design, Edward B. Roche ed., American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

  A “metabolite” is a compound produced by metabolism or biotransformation in the animal or human body, such as biotransformation to a more polar molecule, such as by oxidation, reduction, or hydrolysis, or a conjugate, or Refers to a degradation product or end product of the salt (for reviews of biotransformation, see Goodman and Gilman, “The Pharmaceuticals Basis of Therapeutics, 8th Supplement, Pergamon Press, Gilman et al., (1990)). As used herein, a metabolite of a compound of the present invention or a salt thereof may be a biologically active form of the compound in the body. In one example, a prodrug can be used so that a metabolite that is a biologically active form is released in vivo. In other examples, biologically active forms are successfully discovered. That is, the prodrug design itself was not attempted. Assays for the activity of metabolites of the compounds of the present invention with respect to this disclosure are known to those of skill in the art with reference to this disclosure.

  The compounds of the invention may also exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. For the purposes of the present invention, the solvated form is generally considered equivalent to the unsolvated form.

  The invention is also intended to include compounds made using standard organic synthesis methods such as combinatorial chemistry, or by biological methods such as bacterial digestion, metabolism, enzymatic conversion.

  As used herein, “treating” or “treatment” includes treatment of disease states in humans characterized by abnormal cell proliferation and invasion, including (i) humans, In particular, preventing a disease state from occurring in a human who is expected to be in the disease state but has not yet been diagnosed as having it; (ii) inhibiting the disease state, ie suppressing its onset; (Iii) reducing the disease state, ie causing a regression of the disease state. As is known in the art, adjustments may be required regarding systemic versus local delivery, age, general health, sex, diet, time of administration, drug interactions and severity of the condition. It can be confirmed by routine experimentation by a vendor.

  To elucidate new structural insights useful in understanding the biological activity of the kinases described herein, certain crystallized protein-ligand complexes, particularly c-Met, c-Kit Those skilled in the art will appreciate that, KDR, flt-3, or flt-4 ligand complexes, and their corresponding X-ray structural coordinates can be used. Similarly, important structural features of the protein, particularly the shape of the ligand binding site, can be used in methods for designing or identifying selective modulators of kinases, and in the structure of other proteins with similar features. Useful in elucidation. Such protein-ligand complexes having a compound of the invention as a ligand component are an aspect of the invention.

  Similarly, those of ordinary skill in the art will recognize that such suitable X-ray quality crystals can be used as part of a method for identifying candidate agents that can bind to kinases and modulate kinase activity. I will. Such a method may be characterized by the following aspects: a) Defining a ligand binding domain of a kinase in a conformation in a suitable computer program that creates a three-dimensional structural model of the ligand binding domain (eg, the above preferred B) introducing a three-dimensional structural model of a candidate drug into the computer program, c) introducing a candidate drug model into a ligand Overlaying the model of the binding domain, and d) assessing whether the candidate drug model fits spatially into the ligand binding domain. The aspects a to d are not necessarily performed in the order described above. Such methods further include performing rational drug design with a three-dimensional structural model and selecting potential candidate drugs in conjunction with computer modeling.

  A candidate agent that is determined to be spatially fit in the ligand binding domain is used in a bioactivity assay for kinase modulation, and whether the candidate agent modulates kinase activity in the assay. One of ordinary skill in the art will recognize that may further include determining. Such methods can also include administering a candidate agent determined to modulate kinase activity to a mammal suffering from a condition treatable by kinase modulation as described above.

  Also, one of ordinary skill in the art will recognize that the compounds of the present invention can be used in methods of assessing the ability of a test agent to associate with a molecule or molecular complex comprising a ligand binding domain of a kinase. I will. Such a method may be characterized by the following aspects: a) creating a computer model of the kinase binding pocket using the structural coordinates obtained from a suitable X-ray crystal of the kinase, b) computing the computer. C) performing a fitting operation between the test agent and the computer model of the binding pocket, c) analyzing the result of the fitting operation to determine the relationship between the test agent and the computer model of the binding pocket Quantifying

(Systemic administration)
Administration of the compounds of the present invention or a pharmaceutically acceptable salt thereof can be carried out in pure form or in a suitable pharmaceutical composition with an acceptable mode of administration or similar agent serving a similar utility. Accordingly, administration is preferably in unit dosage form suitable for single administration of precise doses, eg, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions Or in solid, semi-solid, lyophilized powder, or liquid dosage forms such as aerosols, eg, oral, nasal, parenteral (intravenous, intramuscular, or subcutaneous), topical, transdermal, intravaginal, It can be administered intravesically, intrathecally, or rectally.

  The composition may comprise a compound of the invention as an active agent, and additionally at least one other conventional pharmaceutical carrier or excipient such as a pharmaceutical substance, pharmaceutical substance, adjuvant, and the like. The compositions of the invention can be used in combination with anti-cancer agents or other agents that are systemically administered to patients being treated for cancer. Adjuvants include preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, flavoring agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of injectable pharmaceutical forms can be achieved through the use of agents that delay absorption, for example, aluminum monostearate, and gelatin.

  If desired, the pharmaceutical composition of the present invention may contain trace amounts of wetting or emulsifying agents such as citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, pH buffering agents, antioxidants and the like. Supplementary materials may also be included.

  Parenteral suitable compositions are sterile for reconstitution into physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile injectable solutions or dispersions. It may comprise a powder. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, glycerol), suitable mixtures thereof, vegetable oils (such as olive oil) and ethyl oleate And injectable organic esters. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

  One preferred route of administration is oral using a convenient daily dosage regimen that can be adjusted according to the severity of the disease state being treated.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may comprise at least one inert conventional excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) such as starch, lactose, choline Fillers or extenders such as sugar, dextrose, mannitol, and silicic acid; (b) binders such as, for example, cellulose derivatives, starches, lignates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) wetting agents such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, croscarmellose sodium, complex silicates and sodium carbonate, , Dissolution retardants such as paraffin, (f) quaternary ammonium, for example Absorption enhancers such as compounds, (g) cetyl alcohol, and humectants such as glycerol monostearate, magnesium stearate, (h) adsorbents such as kaolin and bentonite, and (i) talc, for example , Mixed with a lubricant such as calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also comprise a buffer.

  The above solid dosage forms can be prepared with coatings and shells such as enteric coatings and others well known in the art. They can contain inhibitors and can also be compositions that release one or more active compounds in certain parts of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compound can also be in microcapsule form, if appropriate, with one or more of the above-described excipients.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms include, for example, carriers such as water, saline, aqueous dextrose, glycerol, ethanol; for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 Solubilizers and emulsifiers such as 1,3-butylene glycol, dimethylformamide; oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and sorbitan A compound of the present invention, or a pharmaceutically acceptable salt thereof and, optionally, a pharmaceutical adjuvant is dissolved or dispersed in a mixture of these substances; Others are prepared such as by forming a suspension.

  In addition to the active compounds, suspending agents are, for example, ethoxylated isosaryl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth gums, or of these substances. Suspending agents such as mixtures can be included.

  Compositions for rectal administration are solid at room temperature but liquid at body temperature and thus melt while in a suitable body cavity and release the active ingredient therein, eg cocoa butter, polyethylene For example, suppositories, which can be prepared by mixing a suitable nonirritating excipient such as a glycol or suppository wax with a compound of the invention.

  Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated to be within the scope of the present invention.

  In general, depending on the intended mode of administration, a pharmaceutically acceptable composition will comprise from about 1% to about 99% by weight of a compound of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1%. Contains% by weight of a suitable pharmaceutical excipient. In one example, the composition comprises between about 5% and about 75% by weight of a compound of the invention, or a pharmaceutically acceptable salt thereof, the remainder being a suitable pharmaceutical excipient. is there.

  Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th edition, (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered, in each case, contains a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease state, in accordance with the teachings of the invention.

  The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be used to determine the activity of the particular compound used, the metabolic stability and length of action of the compound, age, weight, general health, sex, diet, It is administered in a therapeutically effective amount that varies depending on various factors such as mode of administration and administration time, excretion rate, concomitant medication, severity of the particular disease state, and the host being treated. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 mg to about 1,000 mg per day. For a normal human adult weighing about 70 kilograms, an example is a dose in the range of about 0.01 mg to about 100 mg per kilogram body weight per day. However, the specific dose used can vary. For example, the dosage may depend on many factors, such as patient requirements, the severity of the condition being treated, and the pharmacological activity of the compound being used. Determination of the optimal dose for a particular patient is well known to those of ordinary skill in the art.

(Utility of the compound of the present invention as a screening agent)
For example, to use a compound of the invention in a screening method for a candidate agent that binds to a Raf receptor kinase, the protein is bound to a support and the compound of the invention is added to the assay. Alternatively, the compound of the invention is bound to a support before the protein is added. Classes of candidate agents that can search for new binding agents include specific antibodies, non-natural binding agents identified on chemical library screens, and peptide analogs. Of particular interest are screening assays for candidate drugs that are less toxic to human cells. A wide variety of assays can be used for this purpose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (such as phosphorylation assays), and the like.

  For example, determination of the binding of a candidate drug to Raf protein can be performed by a number of methods. In one example, a candidate agent (a compound of the invention) is labeled, for example, with a fluorescent or radioactive moiety, and binding is determined directly. For example, all or part of the Raf protein is bound to a solid support, a labeling substance (eg, a compound of the invention in which at least one atom is replaced by a detectable isotope), and extra reagents By washing and determining whether a certain amount of label is present on the solid support. Various blocking and washing steps known in the art can be used.

  As used herein, “labeling” means that a compound detects a detectable signal (eg, a radioisotope, a fluorescent tag, an enzyme, an antibody, a particle such as a magnetic particle, a chemiluminescent tag, or a specific binding molecule). It means that it is directly or indirectly labeled by the provided label. Specific binding molecules include pairs of biotin and streptavidin, digoxin and antidigoxin, and the like. For specific binding members, usually the complementary member is labeled with a molecule that provides detection by known procedures outlined above. The label can provide a detectable signal directly or indirectly.

In some embodiments, only one of the components is labeled. For example, Raf proteins can be labeled at tyrosine positions with ¹²⁵ I or with fluorophores. Alternatively, more than one component can be labeled with different labels; for example, ¹²⁵ I for the protein and fluorophores for candidate agents.

  The compounds of the present invention can also be used as competitors to screen additional drug candidates. As used herein, a “candidate bioactive agent” or “drug candidate” or grammatical equivalent is any molecule (eg, protein, oligopeptide, small organic molecule, polysaccharide, Nucleotides). They may have the ability to directly or indirectly alter the cell growth phenotype or expression of cell growth sequences, including both nucleic acid and protein sequences. In other cases, changes in cell growth protein binding and / or activity are screened. Where protein binding or activity is screened, in some embodiments, molecules already known to bind to that particular protein are excluded. Exemplary embodiments of the assays described herein include candidate agents, referred to herein as “foreign” reagents, that do not bind to the target protein in the endogenous native state. In one example, the foreign reagent further excludes antibodies against Raf.

  Candidate agents can encompass numerous chemical classes, but typically they are organic molecules having a molecular weight of greater than about 100 daltons and less than about 2,500 daltons. Candidate agents contain functional groups required for structural interaction with proteins, particularly hydrogen bonds and lipophilic bonds, and typically include at least amine groups, carbonyl groups, hydroxyl groups, ether groups, or Contains a carboxyl group, eg, contains at least two functional chemical groups. The candidate agents often comprise cyclical carbon or heterocyclic structures and / or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found in biomolecules such as peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs, or combinations thereof.

  Candidate agents are obtained from a wide variety of sources, such as libraries of synthetic or natural compounds. Numerous means are available for random and specific synthesis of a wide variety of organic compounds and biomolecules, such as, for example, expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Moreover, natural or synthetically produced libraries and compounds are readily modified by conventional chemical, physical and biochemical means. Known pharmacological agents can be subjected to specific or random chemical modifications such as acylation, alkylation, esterification, amidation, etc. to produce structural analogs.

  In one example, candidate agent binding is determined by use of a competitive binding assay. In this example, the competitor is a binding moiety known to bind to Raf, eg, an antibody, peptide, binding partner, ligand, etc. Under certain circumstances, there may be a competitive binding between the candidate agent and the binding moiety, where the binding moiety replaces the candidate agent.

  In some embodiments, the candidate agent is labeled. Either the candidate agent or the competitor, or both, are first added to the Raf protein for a sufficient amount of time to bind, if binding is present. Incubations can be performed at any temperature that facilitates optimal activity, typically between 4 ° C and 40 ° C.

  Incubation periods are selected for optimal activity, but can also be optimized to facilitate rapid high-throughput screening. Typically between 0.1 and 1 hour is sufficient. Excess reagent is generally removed or washed. A second component is then added, followed by the presence or absence of a label component to demonstrate binding.

  In one embodiment, the competitor is added first, followed by the candidate agent. Competitor substitution is an indication that the candidate agent has the ability to bind to Raf and thus bind to Raf and modulate the activity of Raf. In this embodiment, any component can be labeled. Thus, for example, when the competitor is labeled, the presence of the label in the wash solution indicates displacement with the agent. Alternatively, if the candidate agent is labeled, the presence of the label on the support indicates substitution.

  In an alternative embodiment, the candidate agent is added first, followed by incubation and washing, followed by the competitor. The absence of binding by the competitor indicates that the candidate drug is binding to Raf with higher affinity. Thus, when a candidate agent is labeled, the presence of the label on the support may be associated with a lack of binding of the competitor, indicating that the candidate agent has the ability to bind Raf.

  It may be valuable to identify the binding site of Raf. This can be done in various ways. In one embodiment, once it is confirmed that Raf binds to the candidate agent, Raf is fragmented or modified and the assay repeated to identify the components necessary for binding.

  Modulation is tested by screening for candidate agents capable of modulating Raf activity comprising combining the candidate agent with Raf and determining a change in Raf biological activity, as described above. Thus, in this embodiment, the candidate agent should both bind (although this may not be necessary) as well as alter its biological or biochemical activity as defined herein. is there. The methods include both in vitro screening methods and in vivo screening of cells for changes in cell viability, morphology, and the like.

  Alternatively, different screens can be used to identify drug candidates that bind to native Raf but cannot bind to modified Raf.

  The assay can use positive and negative controls. In order to obtain statistically significant results, for example, all control and test samples are performed at least in triplicate. Sample incubation is performed for a time sufficient for the reagent to bind to the protein. Following incubation, the sample is washed to remove non-specific binding material, and then the amount of bound, generally labeled drug, is measured. For example, if a radiolabel is used, the sample can be counted in a scintillation counter to determine the amount of bound compound.

  Various other reagents can be included in the screening assay. These include salts, neutral proteins (eg, albumin), surfactants that can be used to promote optimal protein-protein binding and / or reduce non-specific or background interactions And other reagents. In addition, reagents that improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, antimicrobial agents, etc., can also be used. The mixture of components can be added in any order that provides the requisite binding.

  In order to elucidate new structural information useful for understanding the biological activity of the Raf kinase described herein, certain crystallized protein-ligand complexes (particularly Raf-ligand complexes), Those skilled in the art understand that and their corresponding X-ray structure coordinates may be used. Similarly, important structural features of the aforementioned proteins, in particular the shape of the ligand binding site, can be found in methods for the design or identification of selective modulators of Raf kinase and the structure of other proteins with similar features. Useful in elucidation. Such complexed ligands may include the compounds of the invention described herein.

  Similarly, those skilled in the art will recognize that such suitable X-ray crystals can be used as part of a method to identify candidate agents that can bind to Raf kinase and modulate the activity of Raf kinase. Such a method can be specified by the following aspects: a) Defining a ligand binding domain of Raf kinase in a conformation in a suitable computer program that creates a three-dimensional structural model of the ligand binding domain (eg, as described above B) introducing a three-dimensional structural model of a candidate drug into the computer program, c) introducing a model of the candidate drug Overlaying a model of the ligand binding domain, and d) assessing whether the candidate drug model fits spatially in the ligand binding domain. The aspects a to d are not necessarily performed in the order described above. Such a method may further include performing a rational drug design with a three-dimensional structural model and selecting potential candidate agents in connection with computer modeling.

  In addition, a candidate agent that is determined to be spatially fitted to the ligand binding domain in such a method is used in a bioactivity assay for Raf kinase modulation and whether the candidate agent modulates Raf kinase activity. One of ordinary skill in the art will recognize that it may further include determining in the assay. Such methods can also include administering a candidate agent determined to modulate Raf kinase activity to a mammal suffering from a condition treatable by Raf kinase modulation as described above.

  One skilled in the art will also recognize that the compounds of the present invention can be used in methods of assessing the ability of a test agent to be associated with a molecule or molecular complex comprising the ligand binding domain of Raf kinase. Such a method may be characterized by the following aspects: a) creating a computer model of the Raf kinase binding pocket using structural coordinates obtained from a suitable X-ray crystal of Raf kinase, b) a computer Performing a fitting operation between the test agent and the computer model of the binding pocket, and c) analyzing the result of the fitting operation to determine between the test agent and the computer model of the binding pocket. Quantifying the relevance of

(Abbreviations and their definitions)
The following abbreviations and terms have the indicated meanings throughout.

(Synthesis of compounds)
Scheme 1 shows two general synthetic routes for the compounds of the invention, but is not intended to be limiting. Following this general synthesis, specific examples are described. In the following generalization, specific reaction conditions or details, such as added reagents, catalysts, solvents, reaction temperatures, etc. are not described. The general routes described in connection with the specific examples provided contain sufficient information to enable one skilled in the art to synthesize the compounds of the present invention.

With respect to Scheme 1, suitable reactive intermediates (1) can be prepared, for example, in situ by metal-halogen exchange followed by condensation with a suitable aldehyde precursor, where M is a metal such as lithium or magnesium. For example, alcohol (2) is obtained. According to Formula I, it can be expected that the compound (6) of the present invention is obtained by oxidation of the intermediate (2), or (6) is a derivative known to those skilled in the art for obtaining the compound of the present invention. It may be an intermediate or precursor that requires crystallization. In an alternative synthetic method, proceeding by reaction of a suitable precursor such as cyclic anhydride (3) with an aromatic fragment selected in a regioselective manner, for example by electron affinity aromatic substitution, G ′ Can be obtained, for example, as intermediate (4), which is introduced as a carboxylic acid, which is then transformed by a series of single-step or multi-step synthetic transformations to show intermediate (5). Complete A-ring substituent G can be obtained. One such example is activation of a carboxylate intermediate (4) where G ′ is —CO ₂ H by selected peptide binders, followed by G is C (═) NHR (5). The reaction with a primary amine is obtained. The X ′ and Z ′ groups can then be further synthesized to give (6).

The compounds of the present invention can also be generally prepared according to the pathway outlined in Scheme 2. Accordingly, 2- (4-chloro-3-nitrobenzoyl) benzoic acid (1) is treated with cyanuric acid fluoride to give fluorolactone (2), which is reacted with a series of nucleophilic amines. A lactam product such as (3) can be obtained. Nucleophilic substitution of the chloride can then be carried out by treatment with ammonia in a suitable solvent or with sodium azide, (4a), X═NH ₂ , or (4b, respectively). ), X = N ₃ can be obtained. Reduction of any intermediate can be performed to give (5) under a series of conditions where an appropriate choice such as the choice of R depends on the nature of the substituent. For example, catalytic hydrogenation using palladium on carbon, platinum oxide or Raney nickel can be used. Alternatively, metallic iron or tin (II) chloride can be used as an effective reducing agent. The selection of reagents and reaction conditions applicable to the foregoing transformations is well known in the art, and 1) Larock, Comprehensive Organic Transformations, VCH Publishers, Inc. 2) See March, Advanced Organic Chemistry, Wiley Interscience. Conversion of the resulting phenylenediamine (5) to benzimidazole (6) is accomplished in one step by treatment with 1,3-bis (methoxycarbonyl) 2-methyl-2-thiopseurea with heating in acetic acid. Can be achieved. Alternatively, conversion to (6) can be performed by first treating with methoxycarbonyl isothiocyanate followed by heating in the presence of a suitable carbodiimide such as DCC or EDCI (JC Hazelton et al., Tetrahedron 1995). Year 51 (39), 10771-10794).

In some cases it may be desirable to introduce a carbamate or amide at the 2-position of benzimidazole, where the methoxycarbonyl moiety is replaced by another alkoxycarbonyl group or an acyl group. In such a case, the selected thiopsoid urea reagent can be prepared directly by the general method shown in Scheme 3. For example, carbonate (7) is obtained by reaction of alcohol with 4-nitrophenyl chloroformate, followed by reaction with 2-methyl-2-thiopseure sulfate under basic conditions. An alkoxycarbonyl-2-methyl-2-thiopseudourea reagent (8) is obtained, which can also readily react with phenylenediamines to give the compounds of the present invention. Alternatively, chloroformate, acid chlorides or acid anhydrides and activated esters, etc. can also be reacted with 2-methyl-2-thiopseudourea under appropriate conditions to give monoacylation as in (8) Resulting in derivatives, which are also useful for the synthesis of functionalized 2-aminobenzimidazoles.

An alternative general method for the compounds of the invention that can be used for fast parallel synthesis of a series of lactam derivatives is outlined in Scheme 4. Thus, under standard conditions, conversion of (1) to the corresponding benzyl ester (9) followed by proceeding as outlined in Scheme 1 gives (10) in three steps. Protecting the basic aminobenzimidazole moiety with a suitable protecting group (Greene and Wuts, Protective Groups in Organic Synthesis, Wiley Interscience) and cleaving the benzyl ester by hydrogenation provides the benzoic acid (11) . The lactam can be introduced under a series of amide bond forming conditions well known in the art. Particularly useful is the conversion from (11) to fluorolactone (12) which produces a lactam product even with relatively weakly nucleophilic amines. Subsequently, the synthesis is completed by deprotection of the aminobenzimidazole ring.

The tautomerism of the ring-chain structure of 2-benzoylbenzamides is well established in the art, and therefore the compounds of the present invention such as (6) are suitable for the chain or benzamide (6a) of FIG. ) And cyclic or lactam bodies (6b) are understood to exist in a mechanical equilibrium state. The thermodynamic equilibrium ratio is a function of substrate, temperature, solvent and pH and can be qualitatively determined using appropriate spectroscopic methods such as NMR and UV or IR spectroscopy.

As a further aspect of this tautomerism, the lactam (6b) exists as a racemic mixture of two enantiomers that interconvert via an achiral ring-opened chain tautomer. The kinetics of ring-chain tautomerism and ring tautomer enantiomeric interconversion are also a function of substrate, temperature, solvent and pH, and similarly, kinetic parameters for these processes are known in the art. It is easily measured using well-established spectroscopic and analytical methods. If additional chiral substituents are incorporated into the compounds of the invention, the equilibrium composition of the tautomers of the stereoisomeric ring as well as the kinetics of the interconversion can be affected.

  The following examples serve to more fully describe the method of using the above invention, as well as to describe the best mode contemplated for practicing the various aspects of the invention. It will be understood that these examples do not in any way limit the scope of the invention, but rather are provided for illustrative purposes. All documents cited herein are hereby incorporated by reference in their entirety. In general, each of the examples is described under a corresponding multi-step synthesis scheme. The following specific examples are a list of compounds made in a similar manner.

Example 1: 6- {2-[(4-chlorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine- 3 (4H) -one: 2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonylbenzoic acid (50 mg, 0.17 mmol) in N, N-dimethylformamide To the (1.00 mL) solution, N-methylmorpholine (74 uL, 0.67 mmol) was added, followed by HOAt (55 mg, 0.40 mmol) and HATU (130 mg, 0.34 mmol). The mixture was stirred at room temperature for 30 minutes and then 4-chloro-benzylamine (49 uL, 0.40 mmol) was added. The reaction mixture was then heated at 60 ^° C. for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and the organic layer was washed with brine, 1.0M hydrochloric acid, brine, saturated aqueous sodium bicarbonate and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol to give the title compound (7.3 mg, 15%). MS about _{C 22 H 15 ClN 2 O 4} (EI): 443 (MNa +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
6- (1-hydroxy-2-{[4- (methyloxy) phenyl] methyl} -3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazine- 3 (4H) - _{on-: C 24 H 20 N 2 O} 5 related to ^{MS (EI): 399 (MH} + -H 2 O).

6- (1-hydroxy-2-{[3- (methyloxy) phenyl] methyl} -3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazine- 3 (4H) - _{on-: C 24 H 20 N 2 O} 5 related to _{^{MS (EI): 399 (MH}} + -H 2 O), 417 (MH +).

6- {2-[(4-Bromophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H ) - _{one: C 23 H 17 BrN 2 O} 4 relates ^{MS (EI): 467 (MH} +).

6- {2-[(3-Bromophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H ) - _{one: C 23 H 17 BrN 2 O} 4 relates ^{MS (EI): 467 (MH} +).

6- {2-[(3,4-dichlorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 ( 4H) - _on: MS about _{C 23 H 16 Cl 2 N 2} O 4 (EI): 455 (MH +).

6- {2-[(4-fluorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H ) - _{one: C 23 H 17 FN 2 O} 4 relates ^{MS (EI): 405 (MH} +).

6- (2-{[4-Chloro-3- (trifluoromethyl) phenyl] methyl} -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2H-1 4- benzoxazin -3 (4H) - _{on-: C 24 H 16 ClF 3 N} 2 O 4 relates ^{MS (EI): 489 (MH} +).

6- {1-hydroxy-2-[(4-methylphenyl) methyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H ) - _{one: C 24 H 20 N 2 O} 4 relates ^{MS (EI): 423 (MNa} +).

6- {2-[(3,4-Dimethylphenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H) - _{on-: C 25 H 22 N 2 O} 4 relates ^{MS (EI): 416 (MH} +).

6- (2-{[4- (Dimethylamino) phenyl] methyl} -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazine- 3 (4H) - _{on-: C 25 H 23 N 3 O} 4 relates ^{MS (EI): 444 (MNa} +).

6- [1-Hydroxy-3-oxo-2- (3-phenylpropyl) -2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one _{: C 25 H 22 N 2 O} 4 relates ^{MS (EI): 437 (MNa} +).

6- [1-Hydroxy-3-oxo-2- (2-phenylethyl) -2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, d ₆ -DMSO): 10.60 (s, 1H), 7.76 (d, 1H), 7.58 (dd, 2H), 7.12-7.36 (m, 6H), 6.85 (m, 3H), 4.54 (s, 2H), 3.52 (m, 1H), 3.16 (m, 1H), 2.82 (m, 1H), 2. 62 (m, 1H). C ₂₄ H ₂₀ N ₂ O ₄ relates ^{MS (EI): 401 (MH} +), 384 (MH + -H 2 O).

6- (1-Hydroxy-3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazin-3 (4H) -one: C ₂₂ H ₁₆ MS on the _{N 2 O 4 (EI):} 373 (MH +).

6- [2- (3-Chlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one: MS about _{C 22 H 15 ClN 2 O 4} (EI): 429 (MNa +).

6- [2- (4-Chlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one: MS about _{C 22 H 15 ClN 2 O 4} (EI): 407 (MH +).

6- (2-Butyl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazin-3 (4H) -one: C ₂₀ H ₂₀ MS on the _{N 2 O 4 (EI):} 353 (MH +).

6- [1-Hydroxy-2- (1-methylethyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : MS about _{C 19 H 18 N 2 O 4} (EI): 361 (MNa +).

6- (1-hydroxy-2-{[2- (methyloxy) phenyl] methyl} -3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazine- 3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.53 (s, 1H), 7.75 (d, 1H), 7.53-7.61 (m, 2H), 7.28 (d, 1H), 7.11-7.15 (m, 3H), 6.75-6.88 (m, 5H), 4.52 (s, 2H), 4.51 (d, 1H), 4.09 (d, 1H ), 3.71 (s, 3H); C 24 H 20 N 2 O 5 related to ^{MS (EI): 439 (MNa} +).

6- {2-[(3-chlorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H) -ON: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.52 (s, 1 H), 7.76 (d, 1 H), 7.54-7.62 (m, 2 H), 7.15- 7.30 (m, 6H), 6.78-6.83 (m, 3H), 4.52 (s, 2H), 4.42 (d, 1H), 4.24 (d, 1H); C ₂₃ H ₁₇ ClN ₂ O ₄ relates ^{MS (EI): 421 (MH} +).

6- {2-[(2-chlorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H) - _{^{one: 1 H NMR (400MHz, d}} 6 -DMSO): 10.52 (s, 1H), 7.78 (d, 1H), 7.55-7.64 (m, 2H), 7.16- 7.33 (m, 6H), 6.88 (s, 1H), 6.80 (s, 2H), 4.60 (d, 1H), 4.5 (s, 2H), 4.25 (d _{, 1H); C 23 H 17} ClN 2 O 4 relates ^{MS (EI): 443 (MNa} +).

6- {2-[(3-Fluorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H ) -One: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.52 (s, 1H), 7.75 (d, 1H), 7.53-7.62 (m, 2H), 7.22 -7.30 (m, 3H), 6.96-7.03 (m, 3H), 6.82-6.84 (m, 3H), 4.52 (s, 2H), 4.45 (d _{, 1H), 4.22 (d,} 1H); C 23 H 17 FN 2 O 4 relates ^{MS (EI): 427 (MNa} +).

6- {2-[(2-bromophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H ) -One: ¹ H NMR (400 MHz, d ₆ -DMSO): δ 10.53 (s, 1H), 7.5-7.8 (m, 4H), 7.13-7.32 (m, 5H) , 6.90 (s, 1H), 6.82 (s, 2H), 4.57 (d, 1H), 4.52 (s, 2H), 4.20 (d, 1H); C 23 H 17 MS about _{BrN 2 O 4 (EI):} 489 (MNa +).

6- {2-[(2-fluorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H ) -One: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.50 (s, 1H), 7.77 (d, 1H), 7.55-7.62 (m, 2H), 7.27 -7.30 (m, 2H), 7.20 (s, 2H), 7.0-7.10 (m, 2H), 6.78-6.83 (m, 3H), 4.54 (d , 1H), 4.50 (s, 2H), 4.27 (d, 1H); C 23 H 17 FN 2 O 4 relates ^{MS (EI): 427 (MNa} +).

6- (1-Hydroxy-3-oxo-2-{[2- (trifluoromethyl) phenyl] methyl} -2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazine -3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.51 (s, 1 H), 7.80 (d, 1 H), 7.57-7.66 (m, 3 H) 7.27-7.50 (m, 5H), 6.8-6.86 (m, 3H), 4.72 (d, 1H), 4.50 (s, 2H), 4.35 (d _{, 1H); C 24 H 17} F 3 N 2 O 4 relates ^{MS (EI): 477 (MNa} +).

6- {2-[(5-Bromo-2-fluorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine -3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.52 (s, 1H), 7.80 (d, 1H), 7.55-7.64 (m, 2H) 7.27-7.40 (m, 4H), 7.02-7.07 (m, 1H), 6.80-6.83 (m, 3H), 4.51 (s, 2H), 4 .48 (d, 1H), 4.27 (d, 1H); C 23 H 16 BrFN 2 O 4 relates ^{MS (EI): 506 (MNa} +).

6- {1-hydroxy-2-[(3-nitrophenyl) methyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H ) -One: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.50 (s, 1H), 8.0 (d, 1H), 7.93 (s, 1H), 7.78 (d, 1H) ), 7.47-7.64 (m, 4H), 7.25-7.30 (m, 2H), 6.77 (s, 3H), 4.54 (d, 1H), 4.50 ( _{s, 2H), 4.45 (d} , 1H); C 23 H 17 N 3 O 6 relates ^{MS (EI): 454 (MNa} +).

6- (1-Hydroxy-3-oxo-2-{[3- (trifluoromethyl) phenyl] methyl} -2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazine -3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.50 (s, 1 H), 7.76 (d, 1 H), 7.40-7.62 (m, 6 H) 7.26-7.30 (m, 2H), 6.77-6.82 (m, 3H), 4.50 (d, 1H), 4.49 (s, 2H), 4.37 (d _{, 1H); C 24 H 17} F 3 N 2 O 4 relates ^{MS (EI): 477 (MNa} +).

6- (2-{[2,3-bis (methyloxy) phenyl] methyl} -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2H-1,4 -Benzoxazin-3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.54 (s, 1 H), 7.75 (d, 1 H), 7.55-7.59 (m, 2H), 7.27 (d, 1H), 7.14 (s, 1H), 6.78-6.90 (m, 6H), 4.57 (d, 1H), 4.52 (s, 2H) ), 4.15 (d, 1H) , 3.75 (s, 3H), 3.66 (s, 3H); C 25 H 22 N 2 O 6 relates ^{MS (EI): 469 (MNa} +).

6- {1-hydroxy-2-[(3-iodophenyl) methyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazine-3 (4H ) -One: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.50 (s, 1H), 7.75 (d, 1H), 7.48-7.60 (m, 3H), 7.22. -7.40 (m, 4H), 6.98-7.02 (m, 1H), 6.78-6.80 (m, 3H), 4.53 (s, 2H), 4.35 (d _{, 1H), 4.23 (d,} 1H); C 23 H 17 IN 2 O 4 relates ^{MS (EI): 513 (MH} +).

6- [1-hydroxy-3-oxo-2-({3-[(trifluoromethyl) oxy] phenyl} methyl) -2,3-dihydro-1H-isoindol-1-yl] -2H-1, 4-Benzoxazin-3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.52 (s, 1 H), 7.76 (d, 1 H), 7.56-7.60 (m , 2H), 7.12-7.34 (m, 6H), 6.85 (s, 1H), 6.79 (s, 2H), 4.50 (s, 2H), 4.47 (d, _{1H), 4.29 (d, 1H} ); C 24 H 17 F 3 N 2 O 5 related to ^{MS (EI): 493 (MNa} +).

6- (1-hydroxy-2-{[2- (methylthio) phenyl] methyl} -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazine-3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.13 (s, 1H), 7.77 (d, 1H), 7.50-7.63 (m, 2H), 7 .15-7.31 (m, 5H), 6.82-7.0 (m, 4H), 4.53 (d, 1H), 4.51 (s, 2H), 4.11 (d, 1H) _{), 2.43 (s, 3H)} ; C 24 H 20 N 2 O 4 S about ^{MS (EI): 455 (MNa} +).

6- [2- (3,4-Difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazine-3 (4H) -On: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.53 (s, 1 H), 7.82-7.86 (m, 2 H), 7.57-7.69 (m, 3 H), 7.29-7.45 (m, 3H), 6.83-6.98 (m, 3H), 4.53 (s, 2H); C 22 H 14 F 2 N 2 O 4 MS (EI) for : 431 (MNa ⁺ ).

6- [2- (3,5-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazine-3 (4H) -On: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.55 (s, 1 H), 7.99 (s, 1 H), 7.86 (d, 1 H), 7.58-7.69 ( m, 2H), 7.46-7.49 (m, 2H), 7.30 (d, 1H), 6.85-7.06 (m, 4H), 4.54 (s, 2H); C _{22 H 14 F 2 N 2 O} 4 relates ^{MS (EI): 431 (MNa} +).

6- {1-hydroxy-2- [3- (methylsulfonyl) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazine-3 (4H ) -One: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.55 (s, 1H), 8.30 (s, 1H), 7.87-7.92 (m, 3H), 7.58 -7.72 (m, 4H), 7.32 (d, 1H), 6.83-7.0 (m, 3H), 4.52 (s, 2H), 3.15 (s, 3H); _{C 23 H 18 N 2 O 6} S about ^{MS (EI): 473 (MNa} +).

Ethyl 3- [1-hydroxy-3-oxo-1- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) -1,3-dihydro-2H-isoindole-2 -Yl] benzoate: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.49 (s, 1 H), 8.21 (s, 1 H), 7.54-7.84 (m, 6 H), 7. 41-7.45 (m, 1H), 7.27 (d, 1H), 6.80-6.96 (m, 3H), 4.50 (s, 2H), 4.27 (q, 2H) _{, 1.29 (t, 3H);} C 25 H 20 N 2 O 6 relates ^{MS (EI): 467 (MNa} +).

3- [1-Hydroxy-3-oxo-1- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) -1,3-dihydro-2H-isoindole-2- Yl] benzonitrile: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.49 (s, 1H), 8.06 (s, 1H), 7.83-7.90 (m, 3H), 7. 50-7.66 (m, 4H), 7.29 (d, 1H), 6.80-6.96 (m, 3H), 4.50 (s, 2H); C 23 H 15 N 3 O 4 MS (EI) for: 420 (MNa ⁺ ).

6- [2- (3-Amino-5-chlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazine-trifluoroacetic acid 3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.52 (s, 1H), 7.75 (d, 1H), 7.50-7.63 (m, 3H), 7.21 (d, 2H), 6.75-6.93 (m, 6H), 6.36-6.37 (m, 1H), 4.51 (s, 2H); C 22 H 16 ClN 3 O ₄ on ^{MS (EI): 444 (MNa} +).

6- [2- (3,5-dichlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazine-3 (4H)- On: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.74 (s, 2H), 7.56-7.67 (m, 2H), 7.33 (d , 1H), 7.20-7.21 (m, 1H), 7.0-7.03 (m, 2H), 6.87 (d, 2H), 6.55-6.56 (m, 1H) _{), 4.53 (s, 2H)} ; C 22 H 14 Cl 2 N 2 O 4 relates ^{MS (EI): 463 (MNa} +).

6- {1-hydroxy-2- [3- (1-methylethyl) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.54 (s, 1H), 7.81 (d, 1H), 7.62 (m, 3H), 7.28 (m , 3H), 7.20 (t, 1H), 7.04 (d, 1H), 6.96 (s, 1H), 6.88 (m, 1H), 6.82 (d, 1H), 4 .51 (s, 2H), 2.78 (m, 1H), 1.10 (d, 6H); C 25 H 22 N 2 O 4 relates ^{MS (EI): 437 (MNa} +).

6- {2- [5-Chloro-2- (methyloxy) phenyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine -3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.78 (s, 1 H), 7.89 (d, 1 H), 7.44 (m, 3 H), 6.97 (m, 3H), 6.84 ( s, 2H), 6.53 (s, 1H), 4.63 (s, 2H), 3.71 (s, 3H); C 23 H 17 N 2 O 5 MS (EI) for Cl: 437 (MH ^<+> ).

6- {2- [4-Fluoro-3- (trifluoromethyl) phenyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4- Benzoxazin-3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.55 (s, 1 H), 8.04 (m, 1 H), 7.88 (m, 3 H), 7. 67 (m, 1H), 7.62 (m, 1H), 7.52 (m, 1H), 7.32 (d, 1H), 6.99 (s, 1H), 6.93 (m, 1H) ), 6.86 (m, 1H) , 4.53 (t, 2H); C 23 H 14 N 2 O 5 F 4 relates ^{MS (EI): 481 (MNa} +).

6- [2- (3-Fluoro-5-iodophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazine-3 ( 4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.53 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.85 (d, 1H), 7.67 (m, 1H), 7.59 (m, 1H), 7.52 (m, 1H), 7.44 (m, 1H), 7.29 (d, 1H), 6. 95 (m, 2H), 6.86 (d, 1H), 4.54 (s, 2H); C 22 H 14 N 2 O 4 FI relates ^{MS (EI): 539 (MNa} +).

6- [2- (3-Aminophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, d ₆ -DMSO): 10.54 (s, 1H), 7.83 (d, 1H), 7.65 (m, 2H), 7.57 (m, 1H), 7 .37 (s, 1H), 7.24 (m, 3H), 6.98 (m, 1H), 6.89 (m, 1H), 6.82 (d, 2H), 4.52 (s, _{2H); C 22 H 17 N} 3 O 4 relates ^{MS (EI): 410 (MNa} +).

6- (2-Biphenyl-3-yl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazin-3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.55 (s, 1H), 7.82 (m, 2H), 7.71 (s, 1H), 7.63 (m, 1H), 7. 56 (m, 1H), 7.50 (m, 3H), 7.44 (m, 3H), 7.36 (m, 2H), 7.28 (d, 1H), 7.01 (d, 1H) ), 6.93 (dd, 1H) , 6.83 (d, 1H), 4.50 (s, 2H); C 28 H 20 N 2 O 4 relates ^{MS (EI): 471 (MNa} +).

6- (2- {3-[(Dimethylamino) methyl] phenyl} -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine- 3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.51 (s, 1H), 9.65 (broad s, 1H), 7.77 (m, 2H), 7.63 (M, 4H), 7.41 (m, 1H), 7.28 (m, 2H), 6.94 (s, 1H), 6.78 (m, 2H), 4.49 (s, 2H) , 3.24 (d, 2H), 2.60 (dd, 6H); C 25 H 23 N 3 O 4 relates ^{MS (EI): 430 (MH} +).

6- [2- (3-Fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, CD ₃ OD): 7.87 (d, 1H), 7.65-7.62 (m, 1H), 7.58-7.55 (m, 1H), 7.42 -7.38 (m, 2H), 7.32 (d, 1H), 7.29-7.23 (m, 1H), 7.01-6.96 (m, 2H), 6.92-6 .87 (m, 1H), 6.84-6.82 (m, 1H), 4.51 (s, 2H); C 22 H 15 FN 2 O 4 relates ^{MS (EI): 413 (MH} +).

6- [1-Hydroxy-2- (3-iodophenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, CD ₃ OD): 7.95-7.92 (m, 1H), 7.86 (d, 1H), 7.66-7.62 (m, 1H), 7.59 -7.55 (m, 1H), 7.53-7.49 (m, 2H), 7.32 (d, 1H), 7.06-7.02 (m, 1H), 6.96-6 .94 (m, 2H), 6.85-6.82 (m, 1H), 4.52 (s, 2H); C 22 H 15 IN 2 O 4 relates ^{MS (EI): 520 (MH} +).

6- [2- (3-Bromophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, CD ₃ OD): 7.87 (d, 1H), 7.78-7.74 (m, 1H), 7.66-7.63 (m, 1H), 7.59 -7.55 (m, 1H), 7.52-7.48 (m, 1H), 7.34-7.30 (m, 2H), 7.21-7.16 (m, 1H), 6 .98-6.94 (m, 2H), 6.85-6.83 (m, 1H), 4.52 (s, 2H); C 22 H 15 BrN 2 O 4 relates MS (EI): 474 ( MH ^<+> ).
6- [1-Hydroxy-2- (3-nitrophenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, CD ₃ OD): 8.67-8.65 (m, 1H), 8.08-7.99 (m, 2H), 7.91 (d, 1H), 7.68 -7.49 (m, 4H), 7.35 (d, 1H), 7.03-7.00 (m, 2H), 6.85-6.83 (m, 1H), 4.51 (s _{, 2H); C 22 H 15} N 3 O 6 relates ^{MS (EI): 440 (MH} +).

6- {1-hydroxy-2- [3- (methyloxy) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H ) -One: ¹ H NMR (400 MHz, CD ₃ OD): 7.85 (d, 1H), 7.64-7.61 (m, 1H), 7.57-7.54 (m, 1H), 7.32 (d, 1H), 7.19-7.14 (m, 1H), 7.05-7.03 (m, 2H), 6.97-6.95 (m, 2H), 6. 81 (d, 1H), 6.76-6.74 (m, 1H), 4.50 (s, 2H), 3.70 (s, 3H); C 23 H 18 N 2 O 5 related to MS (EI ): 425 (MH ⁺ ).

6- [1-Hydroxy-2- (3-methylphenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, CD ₃ OD): 7.84 (d, 1H), 7.62-7.58 (m, 1H), 7.55-7.51 (m, 1H), 7.31 (D, 1H), 7.26 (s, 1H), 7.18-7.10 (m, 2H), 7.00-6.92 (m, 3H), 6.78 (d, 1H), 4.47 (s, 2H), 2.26 (s, 3H); C 23 H 18 N 2 O 4 relates ^{MS (EI): 409 (MH} +).

6- (1-Hydroxy-3-oxo-2- {3-[(trifluoromethyl) oxy] phenyl} -2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine -3 (4H) -one: ¹ H NMR (400 MHz, CD ₃ OD): 7.87 (d, 1H), 7.65-7.54 (m, 4H), 7.37-7.32 (m , 2H), 7.05 (d, 1H), 6.99-6.95 (m, 2H), 6.82 (d, 1H), 4.50 (s, 2H); C 23 H 15 F 3 MS on the _{N 2 O 5 (EI):} 479 (MH +).

6- {1-hydroxy-3-oxo-2- [3-[(trifluoromethyl) phenyl] -2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H) -one: ¹ H NMR (400 MHz, CD ₃ OD): 7.96 (s, 1H), 7.88 (d, 1H), 7.82-7.78 (m, 1H), 7. 66-7.62 (m, 1H), 7.59-7.55 (m, 1H), 7.48-7.43 (m, 2H), 7.34 (d, 1H), 6.99- 6.97 (m, 2H), 6.82 (d, 1H), 4.50 (s, 2H); C 23 H 15 F 3 N 2 O 4 relates ^{MS (EI): 463 (MH} +).

3- [1-Hydroxy-3-oxo-1- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) -1,3-dihydro-2H-isoindole-2- Yl] benzenesulfonamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.52 (s, 1H), 8.22 (s, 1H), 7.84-7.82 (m, 2H), 7 .65-7.54 (m, 4H), 7.50-7.46 (m, 1H), 7.40 (s, 2H), 7.29 (d, 1H), 6.96 (s, 1H) ), 6.90-6.88 (m, 1H) , 6.83-6.80 (m, 1H), 4.50 (s, 2H); C 22 H 17 N 3 O 6 MS (EI) for : 474 (MH ^<+> ).

6- [2- (3-Ethylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, d ₆ -DMSO): 7.81 (d, 1H), 7.65-7.55 (m, 3H), 7.34 (s, 1H), 7.27 (d, 2H), 7.21-7.18 (m, 1H), 7.01 (d, 1H), 6.96 (s, 1H), 6.88 (d, 1H), 6.82 (d, 1H) ), 4.51 (s, 2H) , 2.51 (q, 2H), 1.07 (t, 3H); C 24 H 20 N 2 O 4 relates ^{MS (EI): 423 (MH} +).

6- [2- (3-Ethynylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, CD ₃ OD): 7.87 (d, 1H), 7.66-7.62 (m, 2H), 7.59-7.55 (m, 1H), 7.50 -7.45 (m, 1H), 7.33 (d, 1H), 7.29-7.23 (m, 2H), 6.97-6.94 (m, 2H), 6.83 (d , 1H), 4.52 (s, 2H), 3.49 (s, 1H); C 24 H 16 N 2 O 4 relates ^{MS (EI): 419 (MH} +).

6- [1-Hydroxy-2- (3-hydroxyphenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, CD ₃ OD): 7.84 (d, 1H), 7.62-7.58 (m, 1H), 7.55-7.51 (m, 1H), 7.31 (D, 1H), 7.09-7.05 (m, 1H), 6.98-6.90 (m, 4H), 6.80 (d, 1H), 6.62 (dd, 1H), _{4.49 (s, 2H); C} 22 H 16 N 2 O 5 related to ^{MS (EI): 411 (MH} +).

6- {1-hydroxy-3-oxo-2- [3- (phenyloxy) phenyl] -2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazine-3 (4H ) -One: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.52 (s, 1H), 7.81 (d, 1H), 7.69 (s, 1H), 7.65-7.61. (M, 1H), 7.58-7.54 (m, 1H), 7.37-7.24 (m, 6H), 7.15-7.11 (m, 1H), 6.92-6 .79 (m, 6H), 4.53 (s, 2H); C 28 H 20 N 2 O 5 related to ^{MS (EI): 487 (MH} +).

6- (1-hydroxy-3-oxo-2- {3-[(phenylmethyl) oxy] phenyl} -2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazine- 3 (4H) -one: ¹ H NMR (400 MHz, CD ₃ OD): 7.84 (d, 1H), 7.61-7.57 (m, 1H), 7.54-7.50 (m, 1H), 7.33-7.23 (m, 6H), 7.15-7.07 (m, 3H), 6.97 (s, 1H), 6.93 (d, 1H), 6.78 -6.75 (m, 2H), 4.91 (s, 2H), 4.42 (s, 2H); C 29 H 22 N 2 O 5 related to ^{MS (EI): 501 (MH} +).

3- [1-Hydroxy-3-oxo-1- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) -1,3-dihydro-2H-isoindole-2- Yl] benzamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.49 (s, 1 H), 8.09 (s, 1 H), 7.87 (s, 1 H), 7.81 (d, 1 H) ), 7.67 (s, 1H), 7.63-7.54 (m, 4H), 7.36-7.32 (m, 2H), 7.26 (d, 1H), 6.96 ( s, 1H), 6.87-6.85 (m , 1H), 6.80-6.77 (m, 1H), 4.49 (s, 2H); C 23 H 17 N 3 O 5 related to MS (EI): 438 (MH ^<+> ).

6- {1-hydroxy-2- [3- (hydroxymethyl) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -2H-1,4-benzoxazine-3 (4H ) -One: ¹ H NMR (400 MHz, CD ₃ OD): 7.86 (d, 1H), 7.64-7.61 (m, 1H), 7.58-7.54 (m, 1H), 7.47 (s, 1H), 7.35-7.31 (m, 2H), 7.27-7.23 (m, 1H), 7.20-7.18 (m, 1H), 6. 96-6.94 (m, 1H), 6.79 (d, 1H), 4.54 (s, 2H), 4.49 (s, 2H); C 23 H 18 N 2 O 5 related to MS (EI ): 425 (MH ⁺ ).

6- [2- (2-Fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, CD ₃ OD): 7.87 (d, 1H), 7.67-7.63 (m, 1H), 7.60-7.56 (m, 1H), 7.36 -7.27 (m, 3H), 7.11-7.06 (m, 2H), 6.95 (s, 1H), 6.91 (d, 1H), 6.77 (d, 1H), _{4.49 (s, 2H); C} 22 H 15 FN 2 O 4 relates ^{MS (EI): 413 (MH} +).

6- [2- (3-{[2- (dimethylamino) ethyl] oxy} phenyl) 1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1, 4-Benzoxazin-3 (4H) -one: ¹ H NMR (400 MHz, CD ₃ OD): 7.86 (d, 1H), 7.65-7.61 (m, 1H), 7.58-7. 54 (m, 1H), 7.32 (d, 1H), 7.25-7.16 (m, 3H), 6.97-6.93 (m, 2H), 6.87-6.80 ( m, 2H), 4.49 (s , 2H), 4.23 (t, 2H), 3.46 (t, 2H), 2.89 (s, 6H); about _{C 26} H ₂₅ N 3 _{O 5} MS (EI): 460 (MH ^<+> ).

6- [1-Hydroxy-2- (2-methylphenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one : ¹ H NMR (400 MHz, CD ₃ OD): 7.90 (d, 1H), 7.74-7.64 (m, 3H), 7.52-7.48 (m, 1H), 7.29 -7.22 (m, 3H), 6.92-6.80 (m, 2H), 6.69-6.64 (m, 2H), 4.50 (s, 2H), 1.63 (s _{, 3H); C 23 H 18} N 2 O 4 relates ^{MS (EI): 409 (MH} +).

N-methyl-2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] -N-phenylbenzamide: ¹ H NMR (400 MHz, CD ₃ OD): 7 .40-7.30 (m, 4H), 7.24-7.17 (m, 4H), 7.13-7.06 (m, 3H), 6.99 (d, 1H), 4.69 (s, 2H), 3.41 ( s, 3H); C 23 H 18 N 2 O 4 relates ^{MS (EI): 409 (MH} +).

1,1-dimethylethyl 4-{[1-hydroxy-3-oxo-1- (3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) -1,3-dihydro- 2H-isoindol-2-yl] methyl} piperidine-1-carboxylate: ¹ H NMR (400 MHz, CDCl ₃ ): 8.68-8.39 (m, 1H), 7.72-7.64 (m , 1H), 7.51-7.38 (m, 2H), 7.26 (d, 1H), 6.95-6.85 (m, 3H), 4.55 (s, 2H). 02-3.85 (m, 2H), 3.43-3.32 (m, 1H), 2.84-2.67 (m, 1H), 2.65-2.37 (m, 2H), 1.95-1.72 (m, 1H), 1.64-1.50 (m, 2H), 1.39 (s, 9H), 1.16 _{0.99 (m, 2H); C} 27 H 31 N 3 O 6 relates ^{MS (EI): 516 (MNa} +).

6- [2- (2-Chlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.53 (br s, 0.2 H) ring-opened body, 10.46 (br s, 0.8 H) ring-closed body, 7.82 (d, 0.8 H) ) Closed ring, 7.74-6.36 (m, 10.2H), 4.57 (s, 0.4H) open ring, 4.48 (s, 1.6H) closed ring; C ₂₂ H ₁₅ MS about _{ClN 2 O 4 (EI):} 429 (MNa +).

6- [2- (5-Chloro-2-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazine-3 ( 4H) - _{on-: C 23 H 17 ClN 2 O} 4 relates ^{MS (EI): 443 (MNa} +).

6- [2- (3-Chloro-2-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazine-3 ( 4H) - _{on-: C 23 H 17 ClN 2 O} 4 relates ^{MS (EI): 443 (MNa} +).

Trifluoroacetic acid 6- (1-hydroxy-3-oxo-2-piperidin-4-yl-2,3-dihydro-1H-isoindol-1-yl) -2H-1,4-benzoxazine-3 (4H) ON: ¹ H NMR (400 MHz, CD ₃ OD): 7.76 (d, 1H), 7.57 (td, 1H), 7.52 (td, 1H), 7.22 (d, 1H), 7.08-7.01 (m, 2H), 6.93 (d, 1H), 4.57 (s, 2H), 3.62-3.52 (m, 1H), 3.48-3. 41 (m, 1H), 3.39-3.33 (m, 1H), 3.04 (td, 1H), 2.92-2.66 (m, 3H), 2.04-1.96 ( _{m, 1H), 1.68-1.60 (m} , 1H); C 21 H 21 N 3 O 4 relates MS (EI): 380 (MH + .

Example 2: Methyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate : A solution of 2- (4-chloro-3-nitrobenzoyl) benzoic acid (5.0 g, 16.36 mmol) was heated to reflux in 28-30% ammonium hydroxide (100 mL) for 18 hours. The solution was cooled to room temperature and then 6N hydrochloric acid was added until pH7 was reached. The precipitated yellow solid was collected by filtration, washed with water, and dried under reduced pressure to give 2-[(4-amino-3-nitrophenyl) carbonyl] benzoic acid (4.60 g, 98%). C ₁₄ H ₁₀ N ₂ O ₅ related to ^{MS (EI): 288 (MH} +).

A solution of 2-[(4-amino-3-nitrophenyl) carbonyl] benzoic acid (4.60 g, 16.00 mmol) in methanol (300 mL) was heated to reflux for 18 hours in the presence of a catalytic amount of concentrated sulfuric acid. The solution was cooled to room temperature and the solvent was evaporated. The yellow precipitate formed was collected by filtration, washed with water and dried under reduced pressure to give methyl 2-[(4-amino-3-nitrophenyl) carbonyl] benzoate (4.8 g, quantitative). C ₁₅ H ₁₂ N ₂ O ₅ related to ^{MS (EI): 301 (MH} +).

A solution of methyl 2-[(4-amino-3-nitrophenyl) carbonyl] benzoate (420 mg, 1.39 mmol) in a tetrahydrofuran-ethyl acetate (1: 1, 20 mL) mixture was added 10% Pd-C (10 mg). Hydrogenated above for 18 hours. The catalyst was removed by filtration and the filtrate was concentrated to give methyl 2-[(3,4-diaminophenyl) carbonyl] benzoate (370 mg, 98%) as a brown powder. MS about _{C 15 H 14 N 2 O 3} (EI): 293 (MNa +).

To a solution of methyl 2-[(3,4-diaminophenyl) carbonyl] benzoate (134 mg, 0.50 mmol) in a mixture of acetonitrile-benzene (1: 1, 5 mL) was added methylisothiocyanate carbonate (70 mg, .0. 60 mmol) was added followed by DCC (153 mg, 0.75 mmol) and the reaction mixture was heated to reflux for 18 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was triturated with diethyl ether (2 ×, 10 mL) and the pale orange solid was filtered off and methyl 2-[(2-{[(methoxy) carbonyl] amino} -1H-benzimidazol-5-yl) carbonyl] benzoate ( 125 mg, 71%). C ₁₈ H ₁₅ N ₃ O ₅ relating ^{MS (EI): 354 (MH} +).

  Methyl 2-[(2-{[(methoxy) carbonyl] amino} -1H-benzimidazol-5-yl) carbonyl] benzoate (125 mg, 0.35 mmol) was mixed with tetrahydrofuran-methanol (3: 1, 12 mL). And a 3.0 M aqueous solution of lithium hydroxide (0.12 mL) was added. The solution was heated to reflux for 10 minutes, then cooled to room temperature and the solvent was concentrated. Excess hydrogen chloride (4M in dioxane) was added and the acidic mixture was concentrated to dryness. The resulting crude 2-[(2-{[(methoxy) carbonyl] amino} -1H-benzimidazol-5-yl) carbonyl] benzoic acid (120 mg) was used without further purification. MS (EI) for C17H13N3O5: 340 (MH +).

2-[(2-{[(methoxy) carbonyl] amino} -1H-benzimidazol-5-yl) carbonyl] benzoic acid (120 mg, 0.35 mmol), HOAt (0.5 M in DMF, 1.06 mL, 0 .53 mmol), N-methylmorpholine (98 uL, 0.71 mmol) and HATU (175 mg, 0.46 mmol) were added benzylamine (64 uL, 0.60 mmol) and the reaction mixture was added at 60 ^° C. for 18 h. Stir. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in a mixture of acetonitrile-chloroform (1: 1, 50 mL), the organic layer was washed with water and brine, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give methyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole. -2-yl} carbamate, trifluoroacetate (5.7 mg) was obtained. C ₁₇ H ₁₃ N ₃ O ₅ relating ^{MS (EI): 429 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
Methyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO), closed ring isomers only: 7.75 (dd, 1H), 7.64 (brs, 1H), 7.58-7.51 (m, 2H), 7.40 (D, 1H), 7.35 (brs, 1H), 7.23 (dd, 1H), 7.16-7.06 (m, 6H), 4.46 (d, 1H), 4.18 (D, 1H), 3.85 (s, 3H); ¹³ C NMR (100 MHz, d ₆ -DMSO), ring-closed isomers only: 166.5, 152.6, 149.3, 144.5, 137 .8, 135.9, 132.5, 130.0, 129.1, 12 _{.5,126.2,122.7,122.4,121.9,112.9,111.1,90.5,53.5,42.5; C 24 H 20 N 4} O 4 relates MS ( EI): 429 (MH ^<+> ).

Methyl [6- (1-hydroxy-3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl) -1H-benzimidazol-2-yl] carbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ): 7.85 (dd, 1H), 7.75 (s, 1H), 7.62 (d, 1H), 7.59 (m, 2H), 7. 49 (2d, 2H), 7.35 (d, 1H), 7.25 (m, 3H), 7.12 (m, 2H), 3.88 (s, 3H). ¹³ C NMR (400 MHz, DMSO-d ₆ ): 53.01, 92.33, 122.74, 122.96, 125.38, 125.62, 128.21, 129.91, 129.48, 133. _{15,136.39,149.62,166.19; C 23 H 18 N 4} O 4 relates ^{MS (EI): 414 (MH} +).

Example 3: 3-hydroxy-3- [2- (methylamino) -1H-benzimidazol-5-yl] -2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one: A solution of 2- (4-chloro-3-nitrobenzoyl) benzoic acid (38.5 g, 0.126 mol) in ammonium hydroxide (33 wt%, 200 mL) was gently heated to reflux and stirred for 24 hours. Additional ammonium hydroxide (200 mL) was added every 5 hours within a 24 hour reaction time. The reaction mixture was cooled to room temperature and 6N hydrochloric acid was added until pH 2 was reached. The precipitated yellow solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain 2-[(4-amino-3-nitrophenyl) carbonyl] benzoic acid (38.8 g, 95%). ¹ H NMR (400 MHz, CD ₃ OD): 8.27 (d, 1H), 8.11 (d, 1H), 7.80 (dd, 1H), 7.72 (td, 1H), 7.65 (td, 1H), 7.39 ( d, 1H), 7.01 (d, 1H); C 14 H 10 N 2 O 5 related to ^{MS (EI): 309 (MNa} +).

2-[(4-Amino-3-nitrophenyl) carbonyl] benzoic acid (9.3 g, 32.4 mmol), HOAt (0.5 M in DMF, 97 mL, 48.7 mmol), N-methylmorpholine (14 mL, 129 mmol) ) And HATU (16 g, 42.0 mmol) were added benzylamine (7.08 mL, 65.0 mmol) and the reaction mixture was stirred at 60 ^° C. for 1 h. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude 3- (4-amino-3-nitrophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one (10 g, 82%) was Used without further purification. MS about _{C 21 H 17 N 3 O 4} (EI): 398 (MNa +).

3- (4-Amino-3-nitrophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindole- in a mixture of tetrahydrofuran-ethyl acetate (1: 1, 20 mL) A solution of 1-one (10 g, 26.6 mmol) was hydrogenated over 10% Pd—C (100 mg) at 40 psi for 18 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO _2, hexanes / ethyl acetate) to give 3- (3,4-aminophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro -1H- isoindole - 1-one (9.0 g, 98%) was obtained as a brown powder. C ₂₁ H ₁₉ N ₃ O ₂ relates ^{MS (EI): 368 (MNa} +).

3- (3,4-Diaminophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one (100 mg, 0.289 mmol) and methyl isothiocyanate (31 mg, To a solution of 0.434 mmol) in tetrahydrofuran (30 mL) was added 1- [3-dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (89 mg, 0.462 mmol) at room temperature. The reaction mixture was heated to 65 ^° C. and stirred for 3 hours, at which time the mixture was cooled to room temperature and partitioned between water and a mixture of acetonitrile-ethyl acetate (1: 9, 200 mL). The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO _2, methanol / dichloromethane) to give 3-hydroxy-3- [2- (methylamino)-1H-benzimidazol-5-yl] -2- (phenylmethyl) -2,3 -Dihydro-1H-isoindol-1-one (3.3 mg) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): 7.79 (d, 1H), 7.54-7.48 (m, 2H), 7.29-7.26 (m, 2H), 7.18- 7.16 (m, 2H), 7.11-7.01 (m, 4H), 6.86 (dd, 1H), 4.57 (d, 1H), 4.34 (d, 1H), 2 _{.96 (s, 3H); C} 23 H 20 N 4 O 2 relates ^{MS (EI): 385 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
3- (2-{[3,5-Bis (methyloxy) phenyl] amino} -1H-benzimidazol-5-yl) -3-hydroxy-2-phenyl-2,3-dihydro-1H-isoindole- 1-on. ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.98 (s, 1H), 7.83 (d, 1H), 7.77 (s, 1H), 7.58 (m, 3H), 7. 52 (d, 2H), 7.42 (s, 1H), 7.24 (m, 4H), 7.12 (m, 3H), 6.61 (s, 1H), 6.41 (s, 1H) ), 4.45 (d, 1H) , 4.18 (d, 1H), 3.82 (s, 6H); C 29 H 24 N 4 O 4 relates ^{MS (EI): 493 (MH} +).

3- (2-{[3,5-Bis (methyloxy) phenyl] amino} -1H-benzimidazol-5-yl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H- Isoindol-1-one. ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.10 (s, 1H), 7.74 (d, 1H), 7.53 (m, 3H), 7.36 (s, 1H), 7. 32 (s, 1H), 7.23 (m, 3H), 7.13 (m, 5H), 6.62 (d, 1H), 6.41 (s, 1H), 4.45 (d, 1H) ), 4.18 (d, 1H) , 3.82 (s, 6H); C 30 H 26 N 4 O 4 relates ^{MS (EI): 507 (MH} +).

Example 4: Methyl {5- [1- (ethyloxy) -3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: 3- (3,4-diaminophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one (1.5 g, 4.34 mmol) and 1 , 3-bis (methoxycarbonyl) -2-methyl-2-thiopseurea (1.8 g, 8.68 mmol) in absolute ethanol (15 mL) was heated to 95 ^° C. and stirred for 18 hours, at which point The reaction mixture was cooled to room temperature. The white precipitate was filtered and the powder was triturated in hot ethanol (50 mL). A white powder was collected by filtration to give methyl {5- [1- (ethyloxy) -3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2. -Yl} carbamate (700 mg) was obtained. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.82-7.81 (m, 1H), 7.58-7.52 (m, 3H), 7.51 (d, 1H), 7.33 -7.16 (m, 6H), 6.90 (d, 1H), 4.75 (d, 1H), 4.75 (d, 1H), 3.79 (d, 1H), 2.74- 2.67 (m, 2H), 0.65 (t, 3H); ¹³ C NMR (100 MHz, d ₆ -DMSO): 166.9, 154.5, 147.8, 145.7, 137.6, 132.6, 131.1, 130.7, 130.6, 129.4, 128.3, 127.8, 126.8, 122.9, 122.8, 118.9, 95.3, 57. _{9,52.4,42.5,14.1; C 26 H 24 N 4} O 4 relates ^{MS (EI): 457 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
3- (2-{[3,5-Bis (methyloxy) phenyl] amino} -1H-benzimidazol-5-yl) -3- (methyloxy) -2- (phenylmethyl) -2,3-dihydro -1H-isoindol-1-one. MS about _{C 31 H 28 N 4 O 4} (EI): 521 (MH +).

3- (2-{[3,5-Bis (methyloxy) phenyl] amino} -1H-benzimidazol-5-yl) -2- (1-methylethyl) -3- (methyloxy) -2,3 -Dihydro-1H-isoindol-1-one. MS about _{C 27 H 28 N 4 O 4} (EI): 473 (MH +).

Example 5: 3- (1H-benzimidazol-5-yl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one: 3- (3,4- A solution of diaminophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one (27 mg, 0.078 mmol) in formic acid (3.2 μL, 0.086 mmol) Heated to 60 ^° C. for 5 hours. The reaction mixture was then heated to 110 ^° C. for an additional 16 hours, at which point the mixture was cooled to room temperature. The reaction mixture is dissolved in a mixture of acetonitrile-ethyl acetate (1: 9, 50 mL) and the organic layer is washed with saturated aqueous sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate, filtered and filtered. The solution was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give 3- (1H-benzimidazol-5-yl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one, trifluoro Acetic acid salt (6.0 mg) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): 9.24 (s, 1H), 7.93-7.88 (m, 2H), 7.59-7.58 (m, 2H), 7.49 ( d, 1H), 7.28-7.27 (m, 1H), 7.26-7.20 (m, 1H), 7.08-7.07 (m, 2H), 6.99-6. 98 (m, 3H), 4.63 (d, 1H), 4.45 (d, 1H); C 22 H 17 N 3 O 2 relates ^{MS (EI): 356 (MH} +).

Example 6: 5- [1-Hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -N-methyl-1H-benzimidazole-2-carboxamide To a suspension of methylamine hydrochloride (732 mg, 10.8 mmol) and methyl chlorooxoacetate (1 mL, 10.8 mmol) in dioxane (10 mL) was slowly added pyridine (2.0 mL). The reaction mixture was stirred at room temperature for 1.5 hours, at which point the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of acetonitrile-ethyl acetate (1: 9, 150 mL), and the organic layer was washed with water and brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. This gave N-methyl-2-oxopropanamide (267 mg, 21%). GCMS about _{C 4 H 7 NO 3: 116} (M +).

N-methyl-2-oxopropanamide (267 mg, 2.26 mmol) was dissolved in N, N-dimethylformamide (2.00 mL) and 3- (3,4-diaminophenyl) -3-hydroxy-2- ( Phenylmethyl) -2,3-dihydro-1H-isoindol-1-one (45 mg, 0.13 mmol) was added. The reaction mixture was heated to 140 ^° C. and stirred for 16 hours, at which time the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by reverse phase HPLC to give 5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -N-methyl-1H-benz. Imidazole-2-carboxamide, trifluoroacetate (9.4 mg) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): 7.91-7.89 (m, 1H), 7.61-7.58 (m, 2H), 7.20-6.96 (m, 9H), 4.48 (d, 1H), 4.36 (d, 1H), 2.73 (s, 3H); C 24 H 20 N 4 O 3 relates ^{MS (EI): 412 (M} +).

Example 7: 3-Hydroxy-3- (2-methyl-1H-benzimidazol-5-yl) -2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one: 3- ( A solution of 3,4-diaminophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one (33 mg, 0.095 mmol) in acetic acid (1 mL) was added in a catalytic amount. In the presence of 6N hydrogen chloride at 110 ^° C. and stirred for 2.5 hours. The reaction mixture was cooled to room temperature and immediately purified by reverse phase HPLC to give 3-hydroxy-3- (2-methyl-1H-benzimidazol-5-yl) -2- (phenylmethyl) -2,3-dihydro- 1H-isoindol-1-one, trifluoroacetate (6.3 mg) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): 7.89-7.87 (m, 1H), 7.81 (brs, 1H), 7.59-7.56 (m, 2H), 7.41 (D, 1H), 7.26-7.24 (m, 1H), 7.18 (dd, 1H), 7.10-7.09 (m, 2H), 7.02-7.00 (m , 3H), 4.59 (d, 1H), 4.46 (d, 1H), 2.82 (s, 3H); C 23 H 19 N 3 O 2 relates ^{MS (EI): 370 (MH} +) .

Example 8: 7- [2- (3-Chlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -3,4-dihydroquinoxaline-2 (1H) -ON: 2- (4-chloro-3-nitrobenzoyl) benzoic acid (0.31 g, 1.00 mmol) and hydrochloric acid glycine ethyl ester in a solution of 4 M aqueous potassium hydroxide (3.8 mL, 15.0 mmol) 0.69 g, 5.00 mmol) suspension was heated to 90 ^° C. for 15 hours. The reaction mixture was cooled to room temperature and treated with 2M hydrochloric acid to adjust the pH to about 5. The mixture was partitioned with ethyl acetate (50 mL) and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the solvent gave 2-({4-[(carboxymethyl) amino] -3-nitrophenyl} carbonyl) benzoic acid (0.26 g, 76% yield) as a white residue. MS about _{C 16 H 12 N 2 O 7} (EI): 342 (M -).

To a solution of 2-({4-[(carboxymethyl) amino] -3-nitrophenyl} carbonyl) benzoic acid (0.26 g, 0.76 mmol) in N, N-dimethylformamide (5.0 mL) was added potassium carbonate ( 0.52 g, 3.80 mmol) was added followed by benzyl bromide (0.22 mL, 1.82 mmol). The reaction mixture was stirred at room temperature for 15 hours. The mixture was poured into ice water and diluted with ethyl acetate (50 mL). The organic layer was separated and washed with water, 2M hydrochloric acid and brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the crude was purified by silica gel flash chromatography (eluent of hexane: ethyl acetate 4: 1 to 3: 2) to give phenylmethyl 2-{[3-nitro-4-({2- Oxo-2-[(phenylmethyl) oxy] ethyl} amino) phenyl] carbonyl} benzoate (0.33 g, 82% yield) was obtained as an amorphous residue. C ₃₀ H ₂₄ N ₂ O ₇ relates ^{MS (EI): 524 (MH} +).

Phenylmethyl 2-{[3-nitro-4-({2-oxo-2-[(phenylmethyl) oxy] ethyl} amino) phenyl] carbonyl} in a tetrahydrofuran-ethyl acetate (1: 1, 50 mL) mixture A solution of benzoate (0.31 g, 0.59 mmol) was hydrogenated in the presence of 10% Pd / C (0.15 g) at 40 psi in a Parr shaker until hydrogen consumption ceased. The catalyst was filtered off and the solvent was evaporated. The resulting crude was converted to its methyl ester by addition of a 2.0 M trimethylsilyldiazomethane solution in hexane (0.3 mL, 0.60 mmol) in a mixture of benzene-methanol (9: 1, 5.0 mL). The reaction was quenched by the addition of a few drops of acetic acid and the solvent was evaporated. The resulting crude was purified by silica gel flash chromatography (eluent of hexane: ethyl acetate 4: 1 to 1: 1) to give methyl 2-[(3-oxo-1,2,3,4-tetrahydroquinoxaline- 6-yl) carbonyl] benzoate (0.12 g, 67% yield) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.06 (s, 1H), 7.83 (dd, 1H), 7.64 (d, 1H), 7.52 (t, 1H), 7. 38 (d, 1H), 7.09 (7.03 (d, 1H), 4.41 (s, 2H), 3.77 (s, 3H); C 17 H 14 N 2 O 4 relates MS (EI ): 311 (MH ⁺ ).

Methyl 2-[(3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl) carbonyl] benzoate (0. 0) in a mixture of tetrahydrofuran-methanol-water (2: 1: 1, 5.0 mL). 10 g, 0.32 mol) was treated with 2M aqueous lithium hydroxide (1.60 mL, 3.20 mmol) at room temperature for 2 hours. The pH was adjusted to 2 by addition of 6M hydrochloric acid and diluted with ethyl acetate (30 mL). The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. A white precipitate formed during the evaporation of the solvent. 2-[(3-Oxo-1,2,3,4-tetrahydroquinoxalin-6-yl) carbonyl] benzoic acid (0.10 g, quantitative) was collected by filtration. MS about _{C 16 H 12 N 2 O 4} (EI): 295 (M -).

To a solution of 2-[(3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl) carbonyl] benzoic acid (50 mg, 0.16 mmol) in N, N-dimethylformamide (2.0 mL) was added HOAt. (40 mg, 0.28 mmol), HATU (90 mg, 0.23 mmol) and NMM (0.1 mL, 0.80 mmol) were added and the reaction mixture was stirred at room temperature for 20 minutes, then 3-chloro-aniline (24 μL, 0 .23 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours. The solvent was evaporated and the resulting crude was purified by reverse phase preparative HPLC (CH ₃ CN / H ₂ O with 0.1% TFA). Fractions were collected and the aqueous solution was lyophilized to give 7- [2- (3-chlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -3,4 -Dihydroquinoxalin-2 (1H) -one (36 mg, 39% yield) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.25 (s, 1H), 10.44 (s, 1H), 8.04 (d, 1H), 7.78 (t, 1H), 7. 59 (d, 1H), 7.47 (m, 2H), 7.43 (dd, 1H), 7.33 (m, 3H), 7.08 (m, 3H), 4.22 (s, 2H) ); MS (EI) for C ₂₂ H ₁₆ ClN ₃ O ₃ : 406 (MH ⁺ ).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
7- [1-Hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -3,4-dihydroquinoxalin-2 (1H) -one. MS about _{C 23 H 19 N 3 O 3} (EI): 386 (MH +).

Example 9: 3-hydroxy-3- (1H-indol-5-yl) -2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one: sodium hydride (0.27 g, To a suspension of 6.6 mmol) in tetrahydrofuran (10 mL), 5-bromoindole (1.0 g, 5.1 mmol) was added at 0 ^° C. The reaction was stirred at room temperature for 30 minutes, then cooled to 0 ^° C. and 2- (trimethylsilyl) ethoxymethyl chloride (1.0 mL, 5.6 mmol) was added. The solution was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous ammonium chloride and diluted with ether. The organic layer was separated and the aqueous layer was extracted (2 × 100 mL ether). The organic layers were combined, washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 20: 1 hexane / ethyl acetate) gave 1.1 g (66%) of 5-bromo-1-({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indole. . ¹ H NMR (400 MHz, CDCl ₃ ): 7.81 (d, 1H), 7.42 (d, 1H), 7.38 (dd, 1H), 7.23 (d, 1H), 6.52 ( dd, 1H), 5.51 (s , 2H), 3.60 (m, 2H), 0.93 (m, 2H), 0.00 (s, 9H); C 14 H 20 NOSiBr relates MS (EI _{): 209 (M-OCH 2} CH 2 Si (CH 3) 3).

To a solution of 5-bromo-1-({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indole (0.96 g, 2.9 mmol) in tetrahydrofuran (30 mL) cooled to −78 ^° C., n- Butyl lithium (1.6 M in hexanes, 2.2 mL, 3.5 mmol) was added. After stirring at −78 ^° C. for 15 minutes, 2-cyanobenzaldehyde (0.58 g, 4.4 mmol in 2 mL tetrahydrofuran) was quickly added. After stirring at −78 ^° C. for 30 minutes, warmed to room temperature, the reaction mixture was quenched with excess saturated aqueous ammonium chloride and then diluted with ethyl acetate. The organic layer was separated and the aqueous layer was extracted (2 × 100 mL ethyl acetate). The organic layers were combined, dried (sodium sulfate), filtered and concentrated in vacuo. By column chromatography (silica gel, 1: 1 hexane / ethyl acetate) 0.68 g (61%) of 2- {hydroxy [1-({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indole-5 [Il] methyl} benzonitrile was obtained. ¹ H NMR (400 MHz, CDCl ₃ ): 7.9 (d, 1H), 7.60 (d, 1H), 7.57 (m, 2H), 7.53 (d, 1H), 7.27 ( m, 2H), 7.10 (dd, 1H), 6.56 (m, 2H), 5.52 (s, 2H), 3.50 (m, 2H), 0.51 (m, 2H), _{0.00 (s, 9H); C} 22 H 26 N 2 O 2 Si relates ^{MS (EI): 379 (MH} +).

To a solution of oxalyl chloride (0.097 mL, 1.1 mmol) in dichloromethane cooled to −60 ^° C., dimethyl sulfoxide (0.16 mL, 2.2 mmol) is added, followed by 2- {hydroxy [1-({[2 -(Trimethylsilyl) ethyl] oxy} methyl) -1H-indol-5-yl] methyl} benzonitrile (0.21 g, 0.55 mmol in 2 mL dichloromethane) was added. Triethylamine (0.46 mL, 3.3 mmol) was added and the solution was warmed to room temperature and stirred for 30 minutes. The reaction mixture was quenched with excess water and diluted with dichloromethane and brine. The layers were separated and the aqueous layer was extracted (2 × 100 mL dichloromethane), dried (sodium sulfate), filtered and concentrated in vacuo. By column chromatography (silica gel, 4: 1 hexanes / ethyl acetate) 0.12 g (58%) of 2-{[1-({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indole-5 Yl] carbonyl} benzonitrile was obtained. ¹ H NMR (400 MHz, CDCl ₃ ): 8.07 (d, 1H), 7.88 (dd, 2H), 7.70 (m, 3H), 7.60 (d, 1H), 7.30 ( d, 1H), 6.65 (m, 1H), 5.56 (s, 2H), 3.53 (m, 2H), 0.95 (m, 2H), 0.00 (s, 9H); ¹³ C NMR (400 MHz, CDCl ₃ ): 194.90 (C═O), 144.16, 140.45, 135.12, 133.07, 131.72, 131.03, 130.81, 129.82 129.66, 127.08, 125.30, 118.39, 112.98, 111.50, 105.56, 77.05, 67.48, 19.09, 0.00.

  2-{[1-({[2- (Trimethylsilyl) ethyl] oxy} methyl) -1H-indol-5-yl] carbonyl in 2.0 mL ethanol and 2.0 mL aqueous sodium hydroxide (20%) } A solution of benzonitrile (0.12 g, 0.32 mmol) was refluxed for 1 hour. The solution was cooled to room temperature and then poured into ice-cold 1M hydrochloric acid solution (to pH 2). The mixture was diluted with ethyl acetate and the layers were separated. The aqueous layer was extracted (2 × 100 mL ethyl acetate) and the combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo to give crude 2-{[1-({[2- (trimethylsilyl) ethyl] oxy } Methyl) -1H-indol-5-yl] carbonyl} benzoic acid was obtained and used in the next step without further purification.

Crude 2-{[1-({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indol-5-yl] carbonyl} benzonitrile (0.32 mmol) was added to N, N-dimethylformamide (1 0.04 mL), 4-methylmorpholine (0.14 mL, 1.3 mmol), HOAt (0.065 g, 0.48 mmol), HATU (0.16 g, 0.42 mmol) and benzylamine (0.070 mL, 0.64 mmol) and heated at 60 ° C. for 12 hours. The solution was diluted with saturated aqueous sodium bicarbonate and ethyl acetate and the layers were separated. The aqueous layer was extracted (2 × 100 mL ethyl acetate) and the combined organic layers were dried (sodium sulfate), filtered and concentrated under reduced pressure. By column chromatography (silica gel, 3: 1 hexanes / ethyl acetate), 0.089 g (58%) of 3-hydroxy-2- (phenylmethyl) -3- [1-({[2- (trimethylsilyl) ethyl] Oxy} methyl) -1H-indol-5-yl] -2,3-dihydro-1H-isoindol-1-one was obtained. ¹ H NMR (400 MHz, d ₆ -CDCl ₃ ): 8.10 (d, 1H), 7.97 (m, 2H), 7.69 (m, 3H), 7.56 (m, 5H), 7 .42 (m, 4H), 7.34 (m, 1H), 5.49 (m, 2H), 3.51 (m, 2H), 0.95 (m, 2H), 0.00 (s, 9H).

3-hydroxy-2- (phenylmethyl) -3- [1-({[2- (trimethylsilyl) ethyl] oxy} methyl) -1H-indol-5-yl] -2,3-dihydro-1H-isoindole The solution of -1-one was dissolved in 1M tetrabutylammonium fluoride in tetrahydrofuran (6.0 mL, 6.0 mmol), and ethylenediamine (0.22 mL, 3.6 mmol) was added to the solution. This solution was heated to 70 ^° C. for 45 minutes. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the combined organic layers were dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification was performed via HPLC (reverse phase, acetonitrile / water with 0.1% trifluoroacetic acid) followed by column chromatography (silica gel, 5% methanol / dichloromethane). The resulting yellow solid was dissolved in ethyl acetate, washed with 10% aqueous citric acid (3x), dried (sodium sulfate), filtered and concentrated in vacuo. By lyophilization, 0.0045 g (4%) of 3-hydroxy-3- (1H-indol-5-yl) -2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one was obtained. Obtained. ¹ H NMR (400 MHz, d ₆ -DMSO): 8.20 (d, 1H), 7.91 (dt, 2H), 7.84 (dt, 1H), 7.75 (d, 1H), 7. 71 (m, 1H), 7.56 (d, 1H), 7.35 (m, 6H), 4.65 (m, 2H); C 23 H 18 N 2 O 2 relates MS (EI): 354 ( MH ^<+> ).

Example 10: 6-{[2- (1H-benzimidazol-2-yl) phenyl] carbonyl} -2H-1,4-benzoxazin-3 (4H) -one: 2-[(3-oxo-3, 4-Dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzoic acid (100 mg, 0.34 mmol.) Was dissolved in DMF (1 mL) and then 4-methylmorpholine (75 uL, 0.7 mmol.). And PyBOP (177 mg, 0.34 mmol) were added and the resulting solution was stirred at room temperature for 15 minutes. O-Phenylenediamine (37 mg, 0.34 mmol) was added to the solution thus obtained, and the mixture was further stirred for 1 hour before being partitioned between ethyl acetate and water. The organic layer was washed with water (3x), 10% aqueous citric acid (2x), saturated aqueous sodium bicarbonate (1x), and brine, then dried over anhydrous sodium sulfate. Part of the residue obtained by filtration and concentration of the organic solution was purified by silica gel flash chromatography (2: 1 ethyl acetate: hexanes to 100% ethyl acetate) to 6- [2- (2-aminophenyl) -1-hydroxy. -3-Oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one (4.0 mg, 3% yield) was obtained. The remainder of the crude product was dissolved in acetic acid (5 mL) and heated to reflux for 1 hour. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and the residue was purified by silica gel flash chromatography (2.5: 1 ethyl acetate: hexanes) to give 6-{[2- (1H-benzimidazol-2-yl) phenyl]. Carbonyl} -2H-1,4-benzoxazin-3 (4H) -one (28 mg, 22% yield) was obtained. 6- [2- (2-Aminophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -2H-1,4-benzoxazin-3 (4H) -one _{: C 22 H 17 N 3 O} 4 relates ^{MS (EI): 388 (MH} +). 6-{[2- (1H-benzimidazol-2-yl) phenyl] carbonyl} -2H-1,4-benzoxazin-3 (4H) -one: ¹ H NMR (400 MHz, d ₆ -DMSO): 12. 84 (brs, 1H), 10.75 (brs, 1H), 8.00 (d, 1H), 7.73 (tr, 1H), 7.59 (tr, 1H), 7.44-7 .37 (m, 3H), 7.32 (s, 1H), 7.15-7.06 (m, 3H), 6.87 (d, 1H), 4.58 (s, 2H). MS about _{C 22 H 15 N 3 O 3} (EI): 370 (MH +).

Example 11: 6-{[2- (3-Phenyl-1,2,4-oxadiazol-5-yl) phenyl] carbonyl} -2H-1,4-benzoxazin-3 (4H) -one: 2 -[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzoic acid (100 mg, 0.34 mmol) was dissolved in DMF (1 mL) and then 4-methyl Morpholine (75 uL, 0.7 mmol.) And PyBOP (177 mg, 0.34 mmol.) Were added and the resulting solution was stirred at room temperature for 15 minutes. To the resulting solution was added N-hydroxybenzene carboxyimidamide (46 mg, 0.34 mmol) and the mixture was stirred for an additional hour before being partitioned between ethyl acetate and water. The organic layer was washed with water (3x), 10% aqueous citric acid (2x), saturated aqueous bicarbonate (1x) and brine, then dried over anhydrous sodium sulfate. Filtration and concentration gave a crystalline solid that was suspended in anhydrous 1: 1 THF: acetonitrile (1 mL), then 1M TBAF in THF (300 uL) was added and the mixture was allowed to cool at room temperature under nitrogen atmosphere at room temperature. Stir for hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was further washed twice with water to obtain a crystalline solid from the organic layer. The solid product was collected by filtration and suspended in methanol. The solid was collected again by filtration, further washed with methanol, and dried under reduced pressure to give 6-{[2- (3-phenyl-1,2,4-oxadiazol-5-yl) phenyl] carbonyl} -2H- 1,4-Benzoxazin-3 (4H) -one (63 mg, 47% yield) was obtained as a white crystalline solid. ¹ H NMR (400 MHz, d ₄ -MeOH): 8.26 (d, 1H), 7.91 (d, 2H), 7.83-7.80 (m, 2H), 7.62 (d, 1H) ), 7.52-7.44 (m, 4H), 7.35 (dd, 1H), 6.96 (d, 1H), 4.61 (s, 2H). C ₂₃ H ₁₅ N ₃ O ₄ relates ^{MS (EI): 398 (MH} +).

Example 12: 3-hydroxy-3- (1H-indazol-5-yl) -2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one: 5-aminoindazole (5.0 g , 38 mmol) and ice (32 g) in water (16 mL) were further cooled in an ice bath. To this slurry was added concentrated hydrochloric acid (16 mL) followed immediately by sodium nitrite (2.9 g in 11 mL water, 41 mmol). After stirring at 0 ° C. for 10 minutes, potassium iodide (7.5 g, 45 mmol) was added and the solution was slowly warmed to 40 ° C. until gas evolution slowed. The reaction mixture was stirred in an oil bath at 50 ° C. for an additional 30 minutes, then cooled to room temperature, 3M aqueous sodium hydroxide (40 mL) was added, followed by 50% aqueous sodium bicarbonate (40 mL). The solution was filtered under reduced pressure and a brown solid was collected, dissolved in 100 mL of tetrahydrofuran, and stirred with 100 mL of dry silica. To this slurry was added hexanes (66 mL) and the mixture was filtered through a celite / glass filter with 40% tetrahydrofuran / hexanes to rinse the silica. Trituration with ethyl acetate yielded 1.6 g (18%) of 5-iodo-1H-indazole. ¹ H NMR (400 MHz, CDCl ₃ ): 10.55 (broad s, 1H), 8.14 (m, 1H), 8.02 (d, 1H), 7.61 (dd, 1H), 7.31 _{(m, 1H); C 7} H 5 N 2 relates ^{MS (EI): 245 (MH} +).

To a slurry of sodium hydride (0.67 g, 17 mmol) in N, N-dimethylformamide (43 mL) cooled to 0 ^° C., 5-iodo-1H-indazole (3.1 g, 13 mmol) was added. After stirring for 15 minutes, triisopropylsilyl chloride (3.4 mL, 17 mmol) was added dropwise and the solution was allowed to warm to room temperature. The solution was diluted with ethyl acetate and water and the layers were separated. The aqueous layer was extracted (2 × 100 mL ethyl acetate) and the combined organic layers were dried (sodium sulfate), filtered and concentrated under reduced pressure. Column chromatography (silica gel, 20: 1 hexanes / ethyl acetate) gave 1.8 g (68%) of 5-iodo-1- [tris (1-methylethyl) silyl] -1H-indazole as a yellow solid. . ¹ H NMR (400 MHz, CDCl ₃ ): 8.14 (d, 1H), 8.11 (d, 1H), 7.55 (dd, 1H), 7.35 (d, 1H), 1.77 ( m, 3H), 1.10 (m, 18H).

A solution of 5-iodo-1- [tris (1-methylethyl) silyl] -1H-indazole (1.8 g, 4.6 mmol) in tetrahydrofuran (9.2 mL) was cooled to −78 ^° C. and n-butyl. Lithium (1.6 M in hexanes, 3.4 mL, 5.5 mmol) was added. After 15 minutes, 2-cyanobenzaldehyde (0.78 g, 6.0 mmol) in 2.0 mL tetrahydrofuran was quickly added and the solution was allowed to warm to room temperature. The reaction mixture was quenched with excess saturated aqueous ammonium chloride and then partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted (2 × 100 mL ethyl acetate). The organic layers were combined, dried (sodium sulfate), filtered, and concentrated under reduced pressure. By column chromatography (silica gel, 3: 1 hexanes / ethyl acetate) 0.17 g (9%) of 2- (hydroxy {1- [tris (1-methylethyl) silyl] -1H-indazol-5-yl} Methyl) benzonitrile was obtained. ¹ H NMR (400 MHz, CDCl ₃ ): 8.20 (s, 1H), 7.95 (m, 1H), 7.69 (s, 1H), 7.51 (m, 3H), 7.23 ( m, 1H), 7.09 (m , 1H), 6.50 (s, 1H), 1.77 (m, 3H), 1.06 (m, 18H); C 24 H 31 N 3 OSi relates MS (EI): 250 (M-SiiPr ₃ ).

A solution of dimethyl sulfoxide (71 μL, 1.0 mmol) in dichloromethane (1.5 mL) was cooled to −60 ^° C. Addition of oxalyl chloride (44 μL, 0.50 mmol) followed by triethylamine (0.29 mL, 2.1 mmol) and 2- (hydroxy {1- [tris (1-methylethyl) silyl] -1H-indazol-5-yl} Methyl) benzonitrile (0.17 g, 0.42 mmol in 2.0 mL dichloromethane) was added. The solution was warmed to room temperature and then diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted (2 × 100 mL ethyl acetate). The organic layers were combined, dried (sodium sulfate), filtered, and concentrated under reduced pressure. By column chromatography (silica gel, 5: 1 hexanes / ethyl acetate), 0.070 g (42%) of 2-({1- [tris (1-methylethyl) silyl] -1H-indazol-5-yl} carbonyl ) Benzonitrile was obtained. ¹ H NMR (400 MHz, CDCl ₃ ): 8.32 (d, 1H), 8.13 (m, 1H), 8.01 (dd, 1H), 7.87 (m, 1H), 7.68 ( m, 5H), 1.81 (m , 3H), 1.13 (d, 18H); C 24 H 29 N 3 OSi relates MS (EI): 248 (M -Si (iPr) 3).

Of 2-({1- [Tris (1-methylethyl) silyl] -1H-indazol-5-yl} carbonyl) benzonitrile in ethanol (2.0 mL) and 20% aqueous sodium hydroxide solution (2.0 mL). The solution was refluxed for 30 minutes. Solid citric acid was added until pH 3-4. The reaction mixture is diluted with ethyl acetate, dried (sodium sulfate), filtered and concentrated under reduced pressure to give 0.19 g (> 100% crude yield) of 2- (1H-indazol-5-ylcarbonyl) benzoic acid. It was. NMR analysis confirmed the simultaneous loss of the triisopropylsilyl protecting group during this step. This crude acid was used in the next step without further purification. ¹ H NMR (400 MHz, d ₄ -MeOH): 8.14 (m, 1H), 8.10 (m, 1H), 8.05 (m, 1H), 7.75 (m, 3H), 7. 63 (d, 1H), 7.57 (m, 1H).

Crude 2- (1H-indazol-5-ylcarbonyl) benzoic acid (theoretical 0.17 mmol), 4-methylmorpholine (0.076 mL, 0.70 mmol) in N, N-dimethylformamide (1.0 mL). , Benzylamine (0.038 mL, 0.35 mmol), HOAt (0.035 g, 0.26 mmol), and HATU (0.086 g, 0.23 mmol) were stirred at 60 ^° C. for 3 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and brine. The layers were separated and the aqueous layer was extracted (3 × 100 mL ethyl acetate). The organic layers were combined, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by HPLC (reverse phase, acetonitrile / water with 0.1% trifluoroacetic acid) followed by direct lyophilization of the pure fractions yielded 0.023 g (28%) of 3-hydroxy-3- (1H-indazole- 5-yl) -2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one, trifluoroacetate was obtained. ¹ H NMR (400 MHz, d ₆ -DMSO): 8.23 (s, 1H), 8.16 (d, 1H), 7.84 (m, 4H), 7.67 (m, 2H), 7. 33 (m, 7H), 4.55 (m, 2H); C 22 H 17 N 3 O 2 relates ^{MS (EI): 356 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
3-Hydroxy-3- (1H-indol-6-yl) -2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one, trifluoroacetate: ¹ H NMR (400 MHz, d _6- DMSO): 11.10 (broad s, 1H), 8.09 (m, 1H), 7.72 (m, 1H), 7.61 (m, 1H), 7.49 (m, 2H) 7.35 (m, 6H), 7.25 (dd, 1H), 6.42 (s, 1H), 4.32 (m, 2H). C ₂₃ H ₁₈ N ₂ O ₂ relates ^{MS (EI): 355 (MH} +).

3-hydroxy-3- (1H-indazol-6-yl) -2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one, trifluoroacetate: ¹ H NMR (400 MHz, d _6- DMSO): 8.17 (d, 1H), 8.10 (d, 1H), 7.86 (m, 2H), 7.74 (dt, 1H), 7.49 (m, 3H), 7.30 (m, 5H), 4.42 (m, 2H); C 22 H 17 N 3 O 2 relates ^{MS (EI): 356 (MH} +).

Example 13: But-3-en-1-yl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H- Benzimidazol-2-yl} carbamate: To a solution of 2-methyl-2-thiopsoid urea sulfate (12 g, 278 mmol) and potassium carbonate (12 g, 138 mmol) in toluene (50 ml) and water (50 ml) at 25 ^° C. with porcine 3-en-1-yl chloroformate (3.0 g, 134 mmol) was added and stirred for 2.5 hours. The biphasic reaction mixture was separated and the organic phase was washed with water (2 × 80 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give but-3-en-1-yl [imino (methylthio) methyl] carbamate (4.0 g, 96%). _{C 7 H 12 N 2 O 2} S about ^{MS (EI): 287 (MH} +).

N, N-dimethylformamide (25 ml) solution of but-3-en-1-yl [imino (methylthio) methyl] carbamate (3.0 g, 15.9 mmol) and but-3-en-1-ylchloroformate To the solution was added sodium hydride (60% in mineral oil, 0.64 g, 16 mmol) in small portions at 0 ^° C. The reaction mixture was immediately warmed to 25 ° C. and stirred for 16 hours, at which point the solution was diluted with diethyl ether (200 ml). The organic layer was washed with water (100 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give dibut-3-en-1-yl [(Z)-(methylthio) methylylidene] bis. The carbamate (1.29 g, 43%) was obtained. _{C 12 H 18 N 2 O 4} S about ^{MS (EI): 287 (MH} +).

3- (3,4-Diaminophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one (250 mg, 0.72 mole) and dibut-3-ene- A solution of 1-yl [(Z)-(methylthio) methylylidene] biscarbamate (289 mg, 0.94 mmol) in acetic acid (10 ml) was heated to 55 ^° C. and stirred for 35 minutes. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (SiO ₂ , ethyl acetate / hexanes) to give an impure product (0.22 g) as a dark gum. The product was purified further by reverse phase HPLC buta-3-en-1-yl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindole -1-yl] -1H-benzimidazol-2-yl} cabbamate trifluoroacetate (145 mg, 35%) was obtained as a white solid. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.59-7.52 (m, 3H), 7.33 (d, 1H), 7.25 (m, 2H) ), 7.20-7.20 (m, 4H), 6.99 (d, 1H), 5.85 (m, 1H), 5.17 (m, 1H), 5.10 (m, 1H) , 4.48 (d, 1H), 4.28 (t, 2H), 4.15 (d, 1H), 2.44 (m, 2H); C 27 H 24 N 4 O 4 MS (EI) for : 469 (MH ^<+> ).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
Piperidin-4-ylmethyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate , Trifluoroacetate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.62-8.49 (br.m, 2H), 8.29-8.12 (br.m, 1H), 7. 75 (dd, 1H), 7.62-7.47 (m, 3H), 7.36-7.06 (m, 8H), 7.02-6.90 (d, 1H), 4.50 ( d, 1H), 4.18-4.03 (m, 3H), 3.01-2.75 (m, 2H), 2.05-1.77 (m, 5H), 1.48-1. 28 (m, 2H).

Piperidin-4-yl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate , Trifluoroacetate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.62-8.42 (br.m, 2H), 7.78-7.73 (dd, 1H), 7.60- 7.48 (m, 3H), 7.34-7.05 (m, 7H), 7.00-6.92 (d, 1H), 5.05-4.93 (br.m, 1H), 4.49 (d, 1H), 4.14 (d, 1H), 3.28-3.03 (br.m, 4H), 2.15-2.00 (br.m, 2H), 1. 91-1.77 (br.m, 2H).

Ethyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.74 (d, 1H), 7.66 (br s, 1H), 7.51-7.43 (m, 3H), 7.31 (d, 1H), 7. 22 (d, 1H), 7.18 (br s, 1H), 7.08-7.01 (m, 6H), 4.35 (d, 1H), 4.38 (q, 2H), 4. 20 (d, 1H), 1.39 (t, 3H); C 25 H 22 N 4 O 4 relates ^{MS (EI): 443 (MH} +).

3- (Methyloxy) butyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.77 (d, 1H), 7.59 (br s, 1H), 7.55 (dd, 2H), 7.35 (d, 1H) ), 7.29 (br s, 1H), 7.19-7.09 (m, 6H), 7.02 (d, 1H), 4.48 (d, 1H), 4.31 (t, 2H) ), 4.16 (d, 1H), 3.41 (m, 1H), 3.23 (s, 3H), 1.81 (m, 2H), 1.11 (d, 3H); C ₂₈ H ₂₈ N ₄ O ₅ relating ^{MS (EI): 501 (MH} +).

Propa-2-in-1-yl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Il} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.77 (d, 1H), 7.58-7.52 (m, 2H), 7.33 (d, 1H), 7. 26 (d, 1H), 7.18-7.10 (m, 6H), 7.00 (d, 1H), 4.90 (s, 2H), 4.48 (d, 1H), 4.16 (d, 1H), 3.68 ( t, 1H); C 28 H 20 N 4 O 4 relates ^{MS (EI): 453 (MH} +).

But-2-yn-1-yl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Il} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.59-7.52 (m, 3H), 7.32 (d, 2H), 7. 29 (brs, 1H), 7.26 (d, 1H), 7.29-7.10 (m, 6H), 6.99 (d, 1H), 4.85 (q, 2H), 4. 48 (d, 1H), 4.16 (d, 1H), 1.86 (t, 3H); C 27 H 24 N 4 O 4 relates ^{MS (EI): 466 (MH} +).

1-methylethyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.73 (d, 1H), 7.57-7.49 (m, 3H), 7.27-7.11 (m, 7H), 6.85 (d, 1H), 4.96 ( m, 1H), 4.51 (d, 1H), 4.10 (d, 1H), 1.28 (d, 6H); C 26 H 24 N 4 O 4 MS (EI) for: 457 (MH ^<+> ).

2-Fluoroethyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₃ -MeCN): 7.76 (m, 1H), 7.70 (brs, 1H), 7.55-7.47 (m, 2H), 7.41 (d, 1H), 7.26 (m, 1H), 7.21-7.10 (m, 6H), 6.98 (d, 1H), 4.63 (d, 1H), 4.63 (dt, 2H) ), 4.53 (dt, 2H) , 4.20 (d, 1H); C 25 H 21 N 4 O 4 relates ^{MS (EI): 461 (MH} +).

Propyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (dd, 1H), 7.61 (brs, 1H), 7.56 (m, 1H), 7.37 (d, 1H), 7.37 ( br s, 1H), 7.26 (d, 1H), 7.19-7.10 (m, 5H), 7.04 (d, 1H), 4.43 (d, 1H), 4.19 ( d, 1H), 4.18 (t , 2H), 1.69 (m, 2H), 0.95 (t, 3H); C 26 H 24 N 4 O 4 relates MS (EI): 457 (MH + ).

Cyclohexyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.59 (brs, 1H), 7.55 (m, 2H), 7.35 (d, 1H), 7.29 ( br s, 1H), 7.26 (d, 1H), 7.19-7.10 (m, 4H), 7.02 (d, 1H), 4.77 (m, 1H), 4.48 ( d, 2H), 4.16 (d , 2H), 1.92 (m, 2H), 1.73 (m, 2H), 1.56-1.23 (M, 6H); C 29 H 28 N ₄ O ₄ on ^{MS (EI): 497 (MH} +).

Tetrahydrofuran-2-ylmethyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate : ¹ H NMR (400 MHz, d ₆ -DMSO): 7.75 (d, 1H), 7.57-7.52 (m, 3H), 7.33 (d, 1H), 7.26 (br s , 1H), 7.24 (d, 1H), 7.17-7.09 (m, 4H), 7.00 (d, 1H), 4.48 (d, 2H), 4.24-4. 04 (m, 4H), 3.77 (q, 1H), 3.67 (q, 1H), 1.97 (m, 1H), 1.85 (m, 2H), 1.63 (m, 1H) _); C 28 H26N ₄ O ₅ relating ^{MS (EI): 499 (MH} +).

Cyclopropylmethyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.75 (d, 1H), 7.58 (br s, 1H), 7.54 (m, 2H), 7.32 (d, 1H), 7. 28 (brs, 1H), 7.24 (d, 1H), 7.17-7.09 (m, 4H), 7.01 (d, 1H), 4.47 (d, 1H), 4. 16 (d, 1H), 4.07 (d, 2H), 1.21 (m, 1H), 0.58 (m, 2H), 0.38 (m, 2H); C 27 H 24 N 4 O MS (EI) for ₄ : 469 (MH ^<+> ).

But-3-en-1-yl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Il} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.59-7.52 (m, 3H), 7.33 (d, 1H), 7. 25 (m, 2H), 7.20-7.20 (m, 4H), 6.99 (d, 1H), 5.85 (m, 1H), 5.17 (m, 1H), 5.10 (m, 1H), 4.48 ( d, 1H), 4.28 (t, 2H), 4.15 (d, 1H), 2.44 (m, 2H); C 27 H 24 N 4 O 4 MS (EI) for: 469 (MH ^<+> ).

2,2,2-trifluoroethyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Il} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.55 (m, 2H), 7.47 (brs, 1H), 7.26 (m , 3H), 7.19-7.10 (m, 4H), 6.98 (d, 1H), 4.81 (q, 2H0, 4.47 (d, 1H), 4.17 (d, 1H) _{); C 25 H 19 F 3} N 4 O 4 relates ^{MS (EI): 497 (MH} +).

Tetrahydrofuran-3-ylmethyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate : ¹ H NMR (400 MHz, d ₆ -DMSO): 11.65 (br s, 1H), 7.74 (d, 1H), 7.57-7.49 (m, 3H), 7.28-7 .11 (m, 7H), 6.87 (d, 1H), 4.80-4.71 (m, 2H), 4.50 (d, 1H), 4.64 (q, 1H), 4. 16-4.02 (m, 3H), 3.49 (dd, 1H), 2.56 (m, 1H), 1.97 (m, 1H), 1.62 (m, 1H); C ₂₈ H _- 26 _N 4 _{O 5} relating ^{MS (EI): 499 (MH} +).

2,3-dihydroxypropyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.58-7.51 (m, 3H), 7.33 (d, 1H), 7.10-7 .04 (m, 5H), 6.99 (d, 1H), 4.46 (d, 1H), 4.26-4.10 (m, 3H), 3.76 (m, 1H), 3. _{42 (dd, 2H); C} 26 H 26 N 4 O 6 relates ^{MS (EI): 489 (MH} +).

N- {5- [2- (3-Chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} -4-piperidin-1-ylbutanamide: ¹ H NMR (400 MHz, CDCl ₃ ): 7.78 (dd, 1H), 7.66 (br s, 1H), 7.43 (m, 2H), 7 .16-699 (m, 6H), 4.50 (d, 1H), 4.30 (d, 1H), 4.15 (d, 1H), 3.52 (d, 1H), 2.72 ( m, 3H), 1.73 (m , 3H), 1.18 (s, 1H); C 30 H 31 N 5 O 4 relates ^{MS (EI): 526 (MH} +).

1,1-dimethylethyl 4-({[({5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benz Imidazol-2-yl} amino) carbonyl] oxy} methyl) piperidine-1-carboxylate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.73 (d, 1H), 7.57-7.43 ( m, 3H), 7.27-7.13 (m, 7H), 6.87 (d, 1H), 4.51 (d, 1H), 4.11 (d, 1H), 4.02 (d , 2H), 2.72 (br s, 2H), 1.84 (br s, 2H), 1.67 (d, 1H), 1.39 (s, 9H), 1.12 (m, 2H) _{; C 34 H 37 N 5 O} 6 relates ^{MS (EI): 612 (MH} +).

Methyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1-methyl-1H-benzimidazol-2-yl} carbamate : ¹ H NMR (400 MHz, CD ₃ OD): 7.87-7.85 (m, 1H), 7.75 (br s, 1H), 7.58-7.54 (m, 2H), 7. 39 (d, 1H), 7.27-7.20 (m, 2H), 7.14-7.12 (m, 2H), 7.09-7.05 (m, 3H), 4.50 ( d, 2H), 3.94 (s , 3H), 3.75 (s, 3H); C 25 H 22 N 4 O 4 relates ^{MS (EI): 443 (MH} +).

2-methylpropyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.84-7.82 (m, 1H), 7.61-7.56 (m, 3H), 7.41 (d, 1H), 7.20 (M, 6H), 7.04 (m, 1H), 4.68 (d, 1H), 4.29-4.24 (m, 2H), 3.85 (d, 1H), 3.46- 3.39 (m, 1H), 2.74-2.70 (m, 1H), 2.66-2.62 (m, 1H), 1.30-1.27 (m, 3H),. _{70-0.67 (m, 3H); C} 27 H 26 N 4 O 4 relates ^{MS (EI): 471 (MH} +).

But-2-yn-1-yl (5- {1-hydroxy-3-oxo-2-[(1R) -1-phenylmethyl] -2,3-dihydro-1H-isoindol-1-yl}- 1H-benzimidazol-2-yl) carbamate: The reported ¹ H NMR (400 MHz, d ₆ -DMSO) is two ring-closed diastereomers and ring-opened isomers: 10.45 (s, 0 .6H), 8.93 (d, 0.3H), 8.76 (d, 0.3H), 7.83-7.76 (m, 1H), 7.74-7.68 (m, 2 .9H), 7.63-7.58 (m, 2H), 7.57-7.51 (m, 3.3H), 7.50-7.34 (m, 6.6H), 7.32. -7.22 (m, 6.4H), 7.19-7.12 (m, 6.5H), 7.02-6.94 (m, 5.3) H), 4.72 (m, 5.3H), 4.52 (q, 0.5H), 4.41 (q, 0.5H), 4.30 (q, 1H), 1.84 (m) , 5.2H), 1.74 (d, 3H), 1.46 (d, 2.4H), 1.34 (d, 1.2H); C 28 H 24 N 4 O 4 MS (EI) for : 481 (MH ⁺ ).

Phenylmethyl (5- {1-hydroxy-3-oxo-2-[(1R) -1-phenylmethyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2- Yl) carbamate: reported ¹ H NMR (400 MHz, d ₆ -DMSO) is two ring-closed diastereomers and ring-opened isomers: 7.70 (br m, 3H), 7.60- 7.39 (m, 26H), 7.23 (t, 3H), 7.16 (br m, 6H), 7.00-6.96 (m, 6H), 5.29-5.26 (m , 4.6H), 4.53 (brm, 0.5H), 4.41 (brm, 0.5H), 1.74 (d, 2.8H), 1.45 (d, 3H), _{1.27 (d, 1.7H); C} 31 H 26 N 4 O 4 relates MS (EI): 51 ^(MH +).

2,2-Dimethyl-3-[(phenylmethyl) oxy] propyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] −1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.75 (dd, 1H), 7.57-7.50 (m, 3H), 7.34 ( d, 1H), 7.30-7.07 (m, 13H), 7.01 (d, 1H), 4.47 (d, 1H), 4.46 (s, 2H), 4.16 (d , 1H), 4.05 (s, 2H), 3.25 (s, 2H), 0.96 (s, 6H); C 35 H 34 N 4 O 5 relating ^{MS (EI): 591 (MH} +) .

2,2-dimethyl-3- (methyloxy) propyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H- Benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.75 (dd, 1H), 7.58-7.51 (m, 3H), 7.36 (d, 1H ), 7.32 (br s, 1H), 7.25 (d, 1H), 7.16-7.09 (m, 5H), 7.03 (d, 1H), 4.47 (d, 1H) ), 4.16 (d, 1H), 4.01 (s, 2H), 3.24 (s, 3H), 3.14 (s, 2H), 0.92 (s, 6H); C ₂₉ H ₃₀ N ₄ O ₅ relating ^{MS (EI): 515 (MH} +).

3-hydroxy-2,2-dimethylpropyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.69-7.53 (m, 3H), 7.37-7.35 (m, 2H), 7.25 (d, 1H), 7.14-7.11 (m, 5H), 7.04 (d, 1H), 4.46 (d, 1H), 4.17 (d, 1H) ), 4.00 (s, 2H) , 3.23 (s, 2H), 0.88 (s, 6H); C 28 H 28 N 4 O 5 relating ^{MS (EI): 501 (MH} +).

Phenylmethyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.74 (dd, 1H), 7.56 (m, 1H), 7.53 (dt, 1H), 7.35-7.46 (m, 6H), 7.31 (d, 1H), 7.24 (m, 2H), 7.08-7.17 (m, 6H), 6.97 (d, 1H), 5.27 (s, 2H), 4 .47 (d, 1H), 4.14 (d, 1H); C 30 H 24 N 4 O 4 relates ^{MS (EI): 505 (MH} +).

2- (Methyloxy) ethyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ): 7.76 (d, 1H), 7.56 (m, 3H), 7.34 (d, 1H), 7.28 (br.s, 1H), 7.26 (d, 1H), 7.15 (m, 5H), 7.00 (d, 1H), 4.48 (d, 1H), 4.35 (m, 2H), 4.15 (d , 1H), 3.61 (m, 2H), 3.29 (s, 3H); C 26 H 24 N 4 O 5 relating ^{MS (EI): 473 (MH} +).

[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-iso Indol-1-yl] -1H-benzimidazol-2-yl} carbamate acetate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76-7.71 (d, 1H), 7.59-7. 46 (m, 3H), 7.28-7.10 (m, 7H), 6.90-6.85 (d, 1H), 4.53-4.47 (d, 1H), 4.35- 4.22 (m, 2H), 4.16-4.02 (m, 3H), 3.77-3.71 (m, 1H), 1.37-1.32 (s, 3H), 1. _{30-1.27 (s, 3H); C} 29 H 28 N 4 O 6 relates MS (EI): 529 (MH ⁺ ).

Example 14: Methyl {5- [1-hydroxy-2- (3-methylphenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: A solution of 2- (4-chloro-3-nitrobenzoyl) benzoic acid (75 g, 0.25 mol) in 28% ammonium hydroxide (250 mL) was heated at 85 ^° C. for 4 days. Addition of 28% ammonium hydroxide (80 mL) was performed 3 times daily. The solution was partially concentrated in vacuo and then cooled in an ice bath. To this solution, 6N hydrochloric acid was added until the pH became slightly acidic. The formed solid was collected by vacuum filtration, washed twice with water (250 mL) and dried to give 2- (4-amino-3-nitrobenzoyl) benzoic acid (72 g, 100%) as a yellow solid. ¹ H NMR (400 MHz, d ₆ -DMSO): 8.09 (br s, 3H), 7.99 (d, 1H), 7.75-7.58 (m, 3H), 7.40 (d, 1H), 7.09 (d, 1H); MS (EI) for C ₁₄ H ₁₀ N ₂ O ₄ : 309 (MNa ⁺ ).

To a mixture of 2- (4-amino-3-nitrobenzoyl) benzoic acid (50 g, 175 mmol) and potassium carbonate (50 g, 350 mmol) in N, N-dimethylformamide (200 ml) was added benzyl bromide (22.8 ml, 192 mmol) was added. The mixture was stirred at 60 ° C. for 16 hours and then partitioned between ethyl acetate (500 mL) and water. The organic portion was washed with 0.2N sodium hydroxide, water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was recrystallized from chloroform and hexanes (1: 1) to give benzyl 2- (4-amino-3-nitrobenzoyl) benzoate (53 g, 81%) as a yellow solid. ¹ H NMR (400 MHz, d ₆ -DMSO): 8.11 (br s, 1H), 8.06-8.01 (m, 2H), 7.79-7.75 (m, 1H), 7. 72-7.65 (m, 2H), 7.46 (d, 1H), 7.28-7.19 (m, 5H), 7.02 (d, 1H), 5.12 (s, 2H) _{; C 21 H 16 N 2 O} 5 related to ^{MS (EI): 377 (MH} +).

To a 1 L three-necked flask equipped with a mechanical stirrer was added benzyl 2- (4-amino-3-nitrobenzoyl) benzoate (50 g, 133 mmole), iron powder (74 g, in tetrahydrofuran (300 mL) and water (200 mL). 1.30 mol) and a mixture of ammonium formate (167 g, 2.60 mol). The mixture was stirred vigorously at 80 ^° C. for 90 minutes, cooled to room temperature and filtered through celite. Celite was washed with ethyl acetate (500 mL) and the filtrate was partitioned. The organic portion was washed with 2N sodium hydroxide (2 × 100 mL), water, brine, dried over sodium sulfate, and concentrated in vacuo to give benzyl 2- (3,4-diaminobenzoyl) benzoate (47 g, 1.30 mol) brown Obtained as an oil. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.94 (d, 1H), 7.70-7.66 (m, 1H), 7.61-7.58 (m, 1H), 7.37 -7.21 (m, 6H), 6.98 (s, 1H), 6.70 (d, 1H), 6.47 (d, 1H), 5.54 (s, 2H), 5.09 ( _{s, 2H), 4.72 (s} , 2H); C 21 H 18 N 2 O 3 about ^{MS (EI): 349 (MNa} +).

A solution of benzyl 2- (3,4-diaminobenzoyl) benzoate (25 g, 72 mmole) and 1,3-bis (methoxycarbonyl) -2-methyl-2-thiopseurea (19.3 g, 94 mmole) in acetic acid (100 ml) was added. And heated to 75 ^° C. for 45 minutes. The solution was cooled to room temperature and concentrated under reduced pressure. The resulting oil was diluted with ethyl acetate (300 mL), washed with 1N sodium hydroxide (200 mL), water (2 × 200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized using ethyl ether and ethyl acetate (2: 1). The solid was isolated by vacuum filtration and washed with ethyl ether to give [5- (2-benzylcarbanoyl-benzoyl) -1H-benzimidazol-2-yl] -carbamic acid methyl ester, 21.4 g, 49.8 mmol. (69%) was obtained as a yellow solid. ¹ H NMR (400 MHz, d ₆ -DMSO): 8.04 (brs, 1H), 7.77-7.68 (m, 3H), 7.52-7.41 (m, 3H), 7. 28-7.10 (m, 5H), 5.05 (s, 2H), 3.76 (s, 3H); C 24 H 20 N 4 O 4 relates ^{MS (EI): 430 (MH} +).

A solution of [5- (2-benzylcarbanoyl-benzoyl) -1H-benzimidazol-2-yl] -carbamic acid methyl ester (21.4 g, 49.8 mmol) in tetrahydrofuran (150 mL) was cooled in an ice bath. . To this solution was added di-t-butyl dicarbonate (33 g, 150 mmol). Next, a solution of N, N-dimethylaminopyridine (6.1 g, 50 mmole) and Hunig's base (8.7 mL, 50 mmol) in tetrahydrofuran (80 mL) was added dropwise. The solution was stirred at 0 ^° C. for 40 minutes and then quenched by pouring onto crushed ice and 1N hydrochloric acid (2: 1). The mixture was partitioned and extracted with diethyl ether (200 mL). The organic portion was washed with water, saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, ethyl acetate / hexanes). The isolated product was concentrated in vacuo to give 25 g, 40 mmol (80%) of a colorless oil that was diluted in ethyl acetate (150 mL). To this solution was added catalytic palladium on carbon (5% wet) and the solution was stirred at ambient temperature for 18 hours under 1 atmosphere of hydrogen gas. The solution was filtered through celite and concentrated in vacuo to give 24 g, 39 mmol (95%) of a pale yellow oil that was diluted in dichloromethane (150 mL) and cooled to 0 ° C. To this solution was added pyridine (3.6 ml, 39 mmol), followed by the dropwise addition of cyanuric fluoride (6.6 g, 49 mmol). The solution was stirred at ambient temperature for 3 hours and then quenched by the addition of water (25 mL). The mixture was stirred for 30 minutes at ambient temperature. The mixture was filtered through celite and washed with dichloromethane (2 × 50 mL). The filtrate was partitioned and the organic portion was washed with ice cold 0.5N hydrochloric acid, water and brine, dried over sodium sulfate, and filtered through a silica gel plug column. The product was isolated and concentrated in vacuo to give 16.9 g, 31 mmol (62% over 3 steps) of a white solid, which was dissolved in 1,2-dichloroethane (12 mL). To this solution was added N′N-dimethylaniline (470 μl, 3.96 mmol) and m-toluidine (198 μl, 185 mmol). The solution was stirred at 65 ^° C. for 15 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was partitioned between 20% aqueous citric acid and ethyl acetate. The organic portion is washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a purple residue that is purified by column chromatography (silica gel, 50% ethyl acetate in hexane). It was. The product was isolated to give 928 mg, 1.48 mmol (80%) of a white solid, which was dissolved in 925 mg (1.47 mmol) in dichloromethane (2 mL). To this solution was added trifluoroacetic acid (1 mL). The solution was stirred at ambient temperature for 30 minutes and then partitioned between saturated sodium bicarbonate and dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was dissolved in acetonitrile and 4N HCl in dioxane (325 μl, 1.2 mmol) was added to the solution. A white precipitate formed and was collected by vacuum filtration. The solid was washed with ether and dried to give 403 mg, 0.94 mmol (64% over 2 steps) of methyl hydrochloride {5- [1-hydroxy-2- (3-methylphenyl) -3-oxo-2,3-dihydro -1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate was obtained. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.85 (d, 1H), 7.79 (br s, 1H), 7.68 (s, 1H), 7.64-7.56 (m, 2H), 7.44 (d, 1H), 7.38 (s, 1H), 7.26-7.21 (m, 3H), 7.15-7.11 (m, 1H), 6.95. (d, 2H), 3.83 ( s, 3H), 2.21 (s, 3H); C 24 H 20 N 4 O 4 relates ^{MS (EI): 429 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
Methyl (5- {1-hydroxy-2- [3-methyl-5- (trifluoromethyl) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole -2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87-7.76 (m, 4H), 7.62-7.51 (m, 3H), 7.29-7 .22 (m, 3H), 7.01-6.99 (d, 1H), 3.76 (s, 0.4H) ring-opened body, 3.72 (s, 2.6H) ring-closed body, 2. 31 (s, 0.4H) open-ring isomer, 2.28 (s, 2.6H) closed-ring _{form; C 25 H 19 F 3 N} 4 O 4 relates ^{MS (EI): 497 (MH} +).

Methyl {5- [2- (3,4-dichlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.01 to 8.00 (d, 1H), 7.87 (b, 1H), 7.85 (b, 1H), 7.66-7.52 (M, 5H), 7.30-7.25 (d, d, 2H), 7.01-7.00 (d, 1H), 3.77 (s, 0.3H) ring-opened product; 73 (s, 2.7H) closed-ring _{form; C 23 H 16 Cl 2 N} 4 O 4 relates ^{MS (EI): 483 (MH} +).

Methyl {5- [2- (3-ethylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.83-7.81 (d, 2H), 7.61-7.47 (m, 4H), 7.38-7.35 (m, 1H), 7.29-7.23 (m, 3H), 7.16-7.11 (dd, 1H), 6.97-6.94 (m, 2H), 3.76 (s, 0.4H) open annulus, 3.72 (s, 2.6H) ring closure member, 2.51-2.45 (q, 2H), 1.06-1.02 (t, 3H); C 25 H 22 N 4 O 4 MS (EI) for: 443 (MH ^<+> ).

Methyl {5- [2- (3-ethynylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.86-7.84 (d, 1H), 7.75-7.71 (dd, 2H), 7.61-7.51 (m, 4H), 7.31-7.18 (m, 4H), 7.00-6.97 (m, 1H), 4.17 (s, 1H), 3.76 (s, 0.1H) ring-opened product, 3 .72 (s, 2.9H) closed-ring _{form; C 25 H 18 N 4 O} 4 relates ^{MS (EI): 439 (MH} +).

Methyl {5- [2- (4-chloro-3-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.84-7.82 (d, 1H), 7.68 (s, 1H), 7.61-7.50 (m, 4H), 7.38-7.35 (d, d, 1H), 7.29-7.25 (m, 3H), 6.98-6.96 (d, 1H), 3.77 (s, 0.3H) ) ring-opening member, 3.72 (s, 2.7H) closed-ring _{form, 2.22 (s, 3H);} C 24 H 19 ClN 4 O 4 relates ^{MS (EI): 439 (MH} +).

Methyl {5- [2- (2,3-dimethylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate : ¹ H NMR (400 MHz, d ₆ -DMSO): 7.88-7.85 (m, 1H), 7.76-7.05 (m, 8.6H), 6.93-6.91 (d , 0.6H) ring-closed body, 6.73-6.69 (t, 0.4H) ring-opened body, 5.95-5.93 (d, 0, 4H) ring-opened body, 3.83 (s, 1.2H) ring-opened body, 3.81 (s, 1.8H) ring-closed body, 2.29 (s, 1.2H) ring-opened body, 2.10 (s, 1.2H) ring-opened body, 2 .04 (s, 1.8H) closed-ring form, 1.34 (s, 1.8H) closed-ring _{form; C 25 H 22 N 4 O} 4 relates MS (EI): 443 ( H ^+).

Methyl {5- [2- (2,3-dihydro-1H-inden-1-yl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benz Imidazole-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76-7.02 (m, 11H), 6.92-6.88 (t, 0.5H), 6. 72-6.70 (d, 0.2H), 6.56-6.54 (d, 2H), 3.77-3.73 (m, 3H), 3.04-2.93 (m, 1H) ) 2.84-2.78 (m, 1H), 2.48-2.22 (m, 1H), 1.78-1.76 (m, 1H); C ₂₆ H ₂₂ N ₄ O ₄ MS (EI): 455 (MH ^<+> ).

Methyl hydrochloride (6- {2- [2-fluoro-3- (methyloxy) phenyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole -2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.88-7.87 (d, 1H), 7.85-7.83 (b, 1H), 7.68-7 .61 (m, 3H), 7.46-7.43 (d, 1H), 7.29-7.28 (d, 1H), 7.19-7.17 (d, 1H), 7.09 -7.05 (m, 2H), 6.97-6.93 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H); about _{C 24} H 19 _FN 4 _{O 5} MS (EI): 463 (MH ^<+> ).

Methyl hydrochloride {6- [2- (2-fluoro-3-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.88-7.86 (d, 1H), 7.82-7.79 (b, 1H), 7.67-7.60 ( m, 3H), 7.44-7.42 (d, 1H), 7.29-7.27 (d, 1H), 7.20-7.14 (m, 3H), 7.03-6. 99 (dd, 1H), 3.83 (s, 3H), 2.12 (s, 3H); C 24 H 19 FN 4 O 4 relates ^{MS (EI): 447 (MH} +).

Methyl trifluoroacetate (6- {2-[(3-bromophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.84-7.86 (m, 1H), 7.51-7.56 (m, 2H), 7.24-7.32 (m , 4H), 7.16-7.18 (m, 3H), 6.95-7.0 (m, 2H), 4.32-4.42 (m, 2H), 3.97 (s, 3H) _{); C 24 H 19 BrN 4} O 4 relates ^{MS (EI): 507 (MH} +).

Methyl trifluoroacetate (5- {2-[(3-chlorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2- Yl) carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.87-7.89 (m, 1H), 7.51-7.55 (m, 2H), 7.31-7.32 (m, 1H), 7.23-7.27 (m, 3H), 7.10-7.13 (m, 2H), 7.04-7.06 (m, 2H), 6.97 (s, 1H) , 4.51 (d, 1H), 4.32 (d, 1H), 3.96 (s, 3H); C 24 H 19 ClN 4 O 4 relates ^{MS (EI): 507 (MH} +).

Methyl trifluoroacetate (5- {2-[(2-fluorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.74-7.78 (m, 2H), 7.44-7.52 (m, 3H), 7.26-7.30 (m , 2H), 7.20-7.24 (m, 1H), 7.12-7.14 (m, 1H), 6.98-7.03 (m, 1H), 6.84-6.87. (M, 1H), 6.64-6.68 (m, 1H), 4.61 (d, 1H), 4.34 (d, 1H), 3.93 (s, 3H); C ₂₄ H ₁₉ MS on _{FN 4 O 4 (EI):} 447 (MH +).

Methyl trifluoroacetate (5- {2-[(2-chlorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2- Yl) carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.81-7.83 (m, 1H), 7.73 (s, 2H), 7.48-7.53 (m, 2H), 7 .29 (d, 1H), 7.15-7.25 (m, 3H), 6.96-7.04 (m, 3H), 4.75 (d, 1H), 4.44 (d, 1H) _{), 3.92 (s, 3H)} ; C 24 H 19 ClN 4 O 4 relates ^{MS (EI): 463 (MH} +).

Methyl trifluoroacetate (5- {2-[(2-bromophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.81 (d, 1H), 7.55-7.63 (m, 3H), 7.47-7.49 (m, 1H) ), 7.30-7.36 (m, 4H), 7.03-7.22 (m, 3H), 4.59 (d, 1H), 4.13 (d, 1H), 3.80 ( _{s, 3H); C 24 H} 19 BrN 4 O 4 relates ^{MS (EI): 507 (MH} +).

Methyl trifluoroacetate (5- {1-hydroxy-2-[(3-methylphenyl) methyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.75 (d, 1 H), 7.65 (s, 1 H), 7.44-7.51 (m, 2 H), 7.34 ( d, 1H), 7.22-7.27 (m, 3H), 6.83-6.92 (m, 4H), 4.43 (d, 1H), 4.18 (d, 1H), 3 .94 (s, 3H), 2.11 (s, 3H); C 25 H 22 N 4 O 4 relates ^{MS (EI): 442 (MH} +).

Methyl trifluoroacetate (5- {1-hydroxy-2-[(4-methylphenyl) methyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.60 (d, 1H), 7.64 (s, 1H), 7.40-7.52 (m, 3H), 7.22- 7.30 (m, 3H), 7.0 (d, 2H), 6.85 (d, 2H), 4.50 (d, 1H), 4.12 (d, 1H), 3.95 (s _{, 3H), 2.17 (s,} 3H); C 25 H 22 N 4 O 4 relates ^{MS (EI): 443 (MH} +).

Methyl trifluoroacetate (5- {1-hydroxy-2-[(2-methylphenyl) methyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.60 (d, 1H), 7.64 (s, 1H), 7.40-7.52 (m, 3H), 7.22- 7.30 (m, 3H), 7.0 (d, 2H), 6.85 (d, 2H), 4.50 (d, 1H), 4.12 (d, 1H), 3.95 (s _{, 3H), 2.17 (s,} 3H); C 25 H 22 N 4 O 4 relates ^{MS (EI): 443 (MH} +).

Methyl trifluoroacetate {5- [2- (3,5-dimethylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.80 (d, 1H), 7.51-7.62 (m, 4H), 7.30 (d, 1H), 7.21 (d, 1H), 7.06-7.11 ( m, 3H), 6.74 (s, 1H), 3.76 (s, 3H), 2.15 (s, 6H); C 25 H 22 MS on the _{N 4 O 4 (EI):} 443 (MH +).

Methyl trifluoroacetate {5- [2- (3,5-dichlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.92 (d, 1H), 7.52-7.64 (m, 4H), 7.26-7.32 (m, 2H), 7. 21-7.22 (m, 1H), 7.08 (s, 1H), 6.85 (d, 2H), 3.95 (s, 3H); C 23 H 16 MS relates Cl ₂ N _{4 O} 4 (EI): 483 (MH ^<+> ).

Methyl (5- {2- [1- (2-fluorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2- Yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.94-7.80 (m, 12H), 4.93-5.03 (m, 1H), 3.76 (s, 1. 2H), 3.74 (s, 1.1H), 3.71 (s, 0.7H), 1.65 (d, 0.6H), 1.56 (d, 1.2H), 1.29 _{(d, 1.2H); C 25} H 21 FN 4 O 4 relates ^{MS (EI): 461 (MH} +).

Methyl (5- {1-hydroxy-3-oxo-2- [1- (2-thienyl) ethyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl ) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.29-7.72 (m, 11H), 4.59-4.73 (m, 1H), 3.76 (s, 1H), 3.72 (d, 2H), 1.80 (d, 1.2H), 1.49 (d, 1.2H), 1.36 (d, 0.6H); C 23 H 20 N 4 O 4 MS (EI) for S: 449 (MH ^<+> ).

Methyl (5- {2- [1- (3-chlorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl ) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.80-7.77 (m, 12H), 4.78-4.82 (m, 0.3H), 4.52-4.53 (M, 0.3H), 4.39-4.40 (m, 0.4H), 3.75 (s, 1H), 3.73 (s, 1H), 3.72 (s, 1H), 1.74 (d, 1H), 1.44 (d, 1H), 1.30 (d, 1H); C 25 H 21 ClN 4 O 4 relates ^{MS (EI): 477 (MH} +).

Methyl [5- (1-hydroxy-3-oxo-2- {1- [3- (trifluoromethyl) phenyl] ethyl} -2,3-dihydro-1H-isoindol-1-yl) -1H-benz Imidazol-2-yl] carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.23-7.84 (m, 12H), 4.92-4.93 (m, 0.3H), 4. 63-4.64 (m, 0.4H), 4.51-4.53 (m, 0.3H), 3.77 (s, 1H), 3.74 (s, 1H), 3.73 ( s, 1H), 1.80 (d , 1H), 1.49 (d, 1H), 1.34 (d, 1H); C 26 H 21 F 3 N 4 O 4 relates MS (EI): 511 ( MH ^<+> ).

Methyl (5- {1-hydroxy-3-oxo-2-[(1R) -1-phenylpropyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl ) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): R-isomer: 6.94-7.80 (m, 13H), 4.57-4.63 (m, 1H), 3.76 ( s, 2H), 3.74 (s, 0.5H), 3.72 (s, 0.5H), 1.66-1.70 (m, 2H), 0.78 (t, 3H); C ₂₆ H ₂₄ N ₄ O ₄ relates ^{MS (EI): 457 (MH} +).

Methyl (5- {1-hydroxy-3-oxo-2-[(1S) -1-phenylpropyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl ) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): S-isomer: 6.92-7.77 (m, 13H), 4.55-4.61 (m, 1H), 3.75 ( s, 2H), 3.73 (s, 0.5H), 3.71 (s, 0.5H), 1.60-1.67 (m, 2H), 0.78 (t, 3H); C ₂₆ H ₂₄ N ₄ O ₄ relates ^{MS (EI): 457 (MH} +).

Methyl (5- {2- [1- (3-chloro-2-methylphenyl) ethyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benz Imidazole-2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.94-7.84 (m, 11H), 5.00-5.04 (m, 1H), 3.76 ( s, 2H), 3.74 (s, 0.5H), 3.72 (s, 0.5H), 2.20 (s, 3H), 1.66 (d, 0.44), 1.59 (d, 0.40H), 1.26 ( d, 2.16H); C 26 H 23 ClN 4 O 4 relates ^{MS (EI): 491 (MH} +).

Methyl (5- {1-hydroxy-2- [1- (4-methyl-2-thienyl) ethyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole -2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.56-7.75 (m, 10H), 4.56-4.66 (m, 1H), 3.77 (s , 1H), 3.73 (d, 2H), 2.10 (d, 2H), 1.92 (d, 1H), 1.78 (d, 1H), 1.47 (d, 1H), 1 _{.33 (d, 1H); C} 24 H 22 N 4 O 4 S about ^{MS (EI): 463 (MH} +).

Methyl (5- {2- [1- (4-bromo-2-thienyl) ethyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole -2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.86-7.68 (m, 10H), 4.58-4.70 (m, 1H), 3.75 (s , 0.6H), 3.73 (d, 2.4H), 1.78 (d, 1.2H), 1.47 (d, 1.2H), 1.35 (s, 0.6H); _{C 23 H 19 BrN 4 O 4} S about ^{MS (EI): 529 (MH} +).

Methyl (5- {2- [1- (4-chloro-2-thienyl) ethyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole -2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.86-7.75 (m, 10H), 4.57-4.69 (m, 1H), 3.77 (s , 1H), 3.73 (d, 2H), 1.78 (d, 1H), 1.47 (d, 1H), 1.36 (d, 1H); C ₂₃ H ₁₉ ClN ₄ O ₄ S MS (EI): 483 (MH ^<+> ).

Methyl hydrochloride (5- {2- [1- (3-chloro-2-thienyl) ethyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benz Imidazol-2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.83-7.80 (m, 10H), 4.92-5.11 (m, 1H), 3.85 ( d, 2H), 3.80 (s , 1H), 1.75 (d, 1H), 1.51 (d, 1H), 1.34 (d, 1H); C 23 H 19 ClN 4 O 4 S MS (EI) for: 483 (MH ^<+> ).

Methyl hydrochloride (5- {2- [1- (5-bromo-2-thienyl) ethyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benz Imidazol-2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.67-7.79 (m, 10H), 4.59-4.69 (m, 1H), 3.85 ( s, 2.2H), 3.80 (s , 0.8H), 1.76 (d, 1H), 1.50 (d, 1H), 1.37 (d, 1H); C 23 H 19 BrN ₄ O ₄ S about ^{MS (EI): 527 (MH} +).

Methyl hydrochloride {5- [2- (4,5-dichloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.33-7.95 (m, 9H), 7.10 (s, 1H), 3.81 (s, 2.5H) _{, 3.79 (s, 0.5H);} C 23 H 15 Cl 2 FN 4 O 4 relates ^{MS (EI): 501 (MH} +).

Methyl trifluoroacetate [5- (1-hydroxy-3-oxo-2- {3-[(1,1,2,2-tetrafluoroethyl) oxy] phenyl} -2,3-dihydro-1H-isoindole -1-yl) -1H-benzimidazol-2-yl] carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): δ 7.27-7.88 (m, 9H), 6.64-7.10 ( m, 3H), 6.10 (s , 1H), 3.77 (s, 3H); C 25 H 18 F 4 N 4 O 5 relating ^{MS (EI): 531 (MH} +).

Methyl trifluoroacetate {5- [1-hydroxy-3-oxo-2- (3-piperidin-4-ylphenyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.95-8.50 (m, 12H), 3.72 (s, 3H), 1.78-1.80 (m, _{6H), 1.66 (s, 4H} ); C 28 H 27 N 5 O 4 relates ^{MS (EI): 498 (MH} +).

Methyl {5- [2- (3-ethenylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.84 (d, 1H), 7.40-7.68 (m, 6H), 7.21-7.28 (m, 4H), 6.99 (D, 1H), 6.56-6.65 (m, 1H), 5.62 (d, 1H), 5.21 (d, 1H), 3.77 (s, 0.5H) 3.72 _{(s, 2.5H); C 25} H 20 N 4 O 4 relates ^{MS (EI): 441 (MH} +).

Methyl trifluoroacetate {5- [2- (3-aminophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.05-7.83 (m, 11H), 6.68 (s, 1H), 3.77 (s, 3H); C ₂₃ H ₁₉ N ₅ O ₄ on ^{MS (EI): 430 (MH} +).

Methyl [5- (1-hydroxy-2- {3- [methyl (phenyl) amino] phenyl} -3-oxo-2,3-dihydro-1H-isoindol-1-yl) -1H-benzimidazole-2 -Yl] carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.80 (d, 1H), 7.48-7.61 (m, 5H), 6.57-7.26 (m, 11H) ), 3.77 (s, 0.3H) , 3.73 (s, 2.7H), 3.13 (s, 3H); C 30 H 25 N 5 O 4 relates MS (EI): 520 (MH ⁺ ).

Methyl hydrochloride {5- [2- (3-ethynyl-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.02-7.80 (m, 11H), 4.51 (s, 1H), 3.77 (s, 3H); C ₂₅ H ₁₇ FN ₄ O ₄ on ^{MS (EI): 457 (MH} +).

Methyl {5- [1-hydroxy-2- (3-morpholin-4-ylphenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.81-7.83 (m, 1H), 7.53-7.60 (m, 4H), 7.23-7.27 (m , 2H), 6.94-7.10 (m, 4H), 6.58-6.71 (m, 1H), 3.77 (s, 0.4H), 3.73 (s, 2.6H) ), 3.65-3.68 (m, 4H) , 2.91-2.93 (m, 4H); C 27 H 25 N 5 O 5 relating ^{MS (EI): 500 (MH} +).

Methyl trifluoroacetate {5- [1-hydroxy-3-oxo-2- (3-pyrrolidin-1-ylphenyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Il} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.81-7.84 (m, 1H), 7.54-7.62 (m, 4H), 7.37 (d, 1H ), 6.97-7.24 (m, 3H), 6.70-6.72 (m, 2H), 6.28-6.30 (m, 1H), 3.80 (s, 3H), 3.05-3.07 (m, 4H), 1.88-1.90 (m, 4H); C 27 H 25 N 5 O 4 relates ^{MS (EI): 484 (MH} +).

Methyl trifluoroacetate [5- (2- {3- [cyclohexyl (methyl) amino] phenyl} -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benz Imidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.85 (d, 3H), 7.56-7.62 (m, 4H), 7.26-7.34 ( m, 3H), 7.00-7.10 (m, 2H), 3.79 (s, 3H), 3.20 (m, 3H), 2.68 (s, 1H), 0.85-1 _{.76 (m, 10H); C} 30 H 31 N 5 O 4 relates ^{MS (EI): 526 (MH} +).

Methyl {5- [2- (3-chloro-2,6-difluorophenyl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.56-8.17 (m, 10H), 3.77 (s, 0.5H), 3.73 (s, 2.5H) _{; C 23 H 15 ClF 2 N} 4 O 4 relates ^{MS (EI): 485 (MH} +).

Methyl [5- (2- {3- [ethyl (phenyl) amino] phenyl} -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Il} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.82 (d, 1H), 7.56-7.60 (m, 3H), 6.67-7.33 (m, 13H) ), 3.79 (s, 3H) , 3.57-3.59 (q, 2H), 0.96 (t, 3H); C 31 H 27 N 5 O 4 relates MS (EI): 534 (MH ⁺ ).

Methyl hydrochloride (5- {1-hydroxy-3-oxo-2- [2- (phenyloxy) phenyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl ) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.82 (d, 1H), 7.10-7.64 (m, 13H), 6.58-6.66 (m, 3H), _{3.76 (s, 3H); C} 29 H 22 N 4 O 5 relating ^{MS (EI): 507 (MH} +).

Methyl hydrochloride {5- [2- (2,5-dimethylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.88-7.94 (m, 11H), 3.83 (s, 2.8H), 3.81 (s, 0.2H), 2 .31 (s, 3H), 1.44 (s, 3H); C 25 H 22 N 4 O 4 relates ^{MS (EI): 443 (MH} +).

Methyl hydrochloride {5- [2- (3-ethynyl-2-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 6.84-7.91 (m, 11H), 3.85 (s, 1H), 3.83 (s, 2H), 2.33 (s, 1H), 1.59 ( s, 3H); C 26 H 20 N 4 O 4 relates ^{MS (EI): 453 (MH} +).

Methyl (5- {1-hydroxy-2- [1- (5-methyl-2-thienyl) ethyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole -2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.95 (d, 0.2H), 7.75-7.16 (m, 7H), 6.95-6.86 (M, 0.8H), 6.79 (d, 0.5H), 6.59-6.51 (m, 1H), 6.33 (d, 0.3H), 6.09 (d, 0 .2H), 4.97 (m, 0.2H), 4.63 (q, 0.3H), 4.54 (q, 0.5H), 3.76 (s, 0.6H), 74 (s, 1.5H), 3.73 (s, 0.9H), 2.40 (s, 1.5H), 2.35 (s, 0.6H), 2.24 (s, .9H), 1.75 (d, 0.9H ), 1.46 (d, 1.5H), 1.32 (d, 0.6H); C 24 H 22 N 4 O 4 S about MS (EI ): 463 (MH ⁺ ).

Methyl (5- {2- [1- (5-chloro-2-thienyl) ethyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole -2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 9.06 (d, 0.2H), 7.76-7.20 (m, 8H), 6.95-6.82 (M, 2H), 6.79 (d, 0.5H), 6.66 (d, 0.6H), 6.19 (d, 0.4H), 4.96 (m, 0.2H), 4.66 (q, 0.4H), 4.58 (q, 0.4H), 3.77 (s, 0.6H), 3.74 (s, 1.2H), 3.73 (s, 1.2H), 1.77 (d, 1.2H ), 1.47 (d, 1.2H), 1.36 (d, 0.6H); C 23 H 19 ClN 4 ₄ S on ^{MS (EI): 483 (MH} +).

Methyl {5- [2- (furan-2-ylmethyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.71 (m, 1H), 7.54-7.40 (m, 3H), 7.35 (d, 1H), 7.22-7.19 (M, 2H), 7.05 (s, 1H), 6.80 (d, 1H), 6.17 (m, 1H), 5.95 (d, 1H), 4.45 (d, 1H) , 4.18 (d, 1H), 3.72 (s, 3H); C 22 H 18 N 4 O 5 relating ^{MS (EI): 419 (MH} +).

Methyl {5- [1-hydroxy-3-oxo-2- (3-thienylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ 1 H NMR (400 MHz, d ₆ -DMSO): 7.73 (m, 1H), 7.57-7.42 (m, 3H), 7.31 (dd, 1H), 7.27-7.23 ( m, 2H), 7.12-7.09 (m, 2H), 6.90 (dd, 1H), 6.86 (d, 1H), 4.49 (d, 1H), 4.11 (d _{, 1H), 3.73 (s,} 3H); C 22 H 18 N 4 O 4 S about ^{MS (EI): 435 (MH} +), 457 (MNa +).

Methyl (5- {1-hydroxy-3-oxo-2- [3- (phenylcarbonyl) phenyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.97-7.84 (m, 1H), 7.75 (s, 1H), 7.71-7.40 (m, 10H), 7 .28 (d, 2H), 7.00 (d, 1H), 3.76 (s, 0.4H), 3.74 (s, 2.6H); C 30 H 22 N 4 O 5 related to MS ( EI): 519 (MH ^<+> ), 541 (MNa ^<+> ).

Methyl hydrochloride {5- [2- (3-ethyl-4-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.85 (m, 1H), 7.78 (br s, 1H), 7.65-7.57 (m, 3H), 7. 41 (d, 1H), 7.37 (dd, 1H), 7.28-7.23 (m, 2H), 7.17 (d, 1H), 7.04 (t, 1H), 3.82 (s, 3H), 3.70-3.20 ( q, 2H), 1.04 (t, 3H); C 25 H 21 FN 4 O 4 relates ^{MS (EI): 461 (MH} +).

Methyl hydrochloride {5- [2- (3-chloro-5-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.10 (m, 1H), 7.89 (d, 1H), 7.72 (s, 1H), 7.67-7.55 (M, 4H), 7.43-7.38 (m, 1H), 7.29 (d, 1H), 7.22-7.18 (m, 2H), 3.81 (s, 3H); MS about _{C 23 H 16 ClFN 4 O 4} (EI): 467 (MH +).

Methyl hydrochloride {5- [2- (5-bromo-2,4-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.90 (m, 2H), 7.75-7.63 (m, 3H), 7.56-7.51 (m, 2H), 7.40 (d, 1H ), 7.32 (d, 1H), 7.09 (d, 1H), 3.82 (s, 3H); about _{C 23 H 15 BrF 2 N 4} O 4 MS (EI): 529, 531 (MH ^<+> ).

Methyl hydrochloride {5- [2- (5-chloro-2,4-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.90 (m, 2H), 7.72-7.55 (m, 5H), 7.39 (d, 1H), 7 .34 (d, 1H), 7.07 (d, 1H), 3.81 (s, 3H); C 23 H 15 ClF 2 N 4 O 4 relates ^{MS (EI): 485,487 (MH} +).

Methyl hydrochloride {5- [2- (3,5-dichloro-4-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.11 (br s, 1H), 7.90 (d, 1H), 7.86 (d, 2H), 7.70- 7.59 (m, 3H), 7.41 (d, 1H), 7.29 (d, 1H), 7.21 (d, 1H), 3.82 (s, 3H); C 23 H 15 Cl MS about _{2 FN 4 O 4 (EI)} : 501,503,505 (MH +).

Methyl {5- [2- (3-chloro-2-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.90-7.23 (m, 9.4H), 6.90-6.81 (m, 1.3H), 6.08 (d , 0.3H), 3.78 (s, 1H), 3.76 (s, 2H), 2.25 (s, 1H), 1.48 (s, 2H); C ₂₄ H ₁₉ ClN ₄ O ₄ MS (EI) for: 463, 465 (MH ^<+> ).

Methyl {5- [2- (5-chloro-2-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.88 (d, 1H), 7.78-7.59 (m, 4H), 7.46-7.23 (M, 5H), 7.09 (br s, 1 H), 6.84 (br s, 1 H), 3.77 (s, 3 H), 1.49 (br, s, 3 H); MS for C ₂₄ H ₁₉ ClN ₄ O ₄ (EI): 463, 465 (MH ^<+> ).

Methyl hydrochloride {5- [2- (5-chloro-2,3-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.92-7.89 (m, 2H), 7.72-7.62 (m, 3H), 7.51 (br s , 1H), 7.34-7.31 (m, 3H), 7.00 (d, 1H), 3.77 (s, 0.4H), 3.76 (s, 2.6H); C 23 MS regarding _{H 15 ClF 2 N 4 O 4} (EI): 485,487 (MH +).

Methyl hydrochloride {5- [2- (5-ethynyl-2-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.891 (d, 1H), 7.76-7.60 (m, 4H), 7.44-7.29 (m, 4H) 7.06 (d, 1H), 6.91 (d, 1H), 4.22 (s, 1H), 3.81 (s, 3H), 1.52 (s, 3H); C ₂₆ H ₂₀ MS on the _{N 4 O 4 (EI):} 453 (MH +).

Phenylmethyl 2-[(2-{[(methyloxy) carbonyl] amino} -1H-benzimidazol-5-yl) carbonyl] benzoate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.02 (d, 1H), 7.75 (tr, 1H), 7.68-7.64 (m, 2H), 7.47-7.41 (m, 3H), 7.22-7.11 (m, 5H) , 5.03 (s, 2H), 3.74 (s, 3H). C ₂₄ H ₁₉ N ₃ O ₅ relating ^{MS (EI): 430 (MH} +).

Methyl {5- [1-hydroxy-3-oxo-2- (2-thienylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate, tri Fluoroacetate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.74 (d, 1H), 7.55-7.50 (m, 3H), 7.28 (d, 1H), 7.24 -7.20 (m, 3H), 6.93 (brd, 1H), 6.72 (m, 1H), 6.80 (m, 1H), 4.49 (dd AB, 2H), 3. 78 (s, 3H). _{C 22 H 18 N 4 O 4} S about ^{MS (EI): 435 (MH} +).

Methyl {5- [1-hydroxy-3-oxo-2- (2-phenylethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate, tri Fluoroacetate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.74 (d, 1H), 7.61 (s, 1H), 7.55-7.51 (m, 2H), 7.43 (D, 1H), 7.26-7.04 (m, 8H), 3.80 (s, 3H), 3.52 (ddd, 1H), 3.11 (ddd, 1H), 2.81 ( ddd, 1H), 2.60 (ddd, 1H). C ₂₅ H ₂₂ N ₄ O ₄ relates ^{MS (EI): 443 (MH} +).

Methyl [5- (1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate, trifluoroacetate: ¹ H NMR (400 MHz , D ₆ -DMSO): 9.29 (s, 1H), 7.67 (s, 1H), 7.64 (d, 1H), 7.53-7.43 (m, 3H), 7.31 (d, 1H), 7.25 ( d, 1H), 7.00 (br s, 1H), 3.81 (s, 3H) .C 17 H 14 N 4 O 4 relates MS (EI): 339 ( MH ^<+> ).

Methyl {5- [2- (2,3-dihydro-1H-inden-2-yl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benz Imidazol-2-yl} carbamate, trifluoroacetate salt: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.73 (s, 1H), 7.72 (s, 1H), 7.55-7.48 (M, 3H), 7.37 (brs, 1H), 7.24-7.17 (m, 3H), 7.11-7.09 (m, 3H), 4.07-3.99 ( m, 2H), 3.82 (s, 3H), 3.65-3.57 (m, 2H), 2.98 (dd, 1H). C ₂₆ H ₂₂ N ₄ O ₄ relates ^{MS (EI): 455 (MH} +).

Methyl {5- [1-hydroxy-3-oxo-2- (pyridin-4-ylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate, Trifluoroacetate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.67 (d, 2H), 7.82 (d, 1H), 7.72 (d, 2H), 7.65-7. 57 (m, 3H), 7.43 (br s, 1H), 7.36 (d, 1H), 7.33 (d, 1H), 7.02 (d, 1H), 4.56 (dd AB) , 2H), 3.80 (s, 3H). MS about _{C 23 H 19 N 5 O 4} (EI): 430 (MH +).

Methyl {5- [1-hydroxy-3-oxo-2- (pyridin-3-ylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate, Trifluoroacetate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.54 (d, 1H), 8.51 (s, 1H), 8.00 (d, 1H), 7.61-7. 54 (m, 4H), 7.33 (d, 1H), 7.29 (d, 1H), 6.97 (d, 1H), 4.47 (dd AB, 2H), 3.80 (s, 3H). MS about _{C 23 H 19 N 5 O 4} (EI): 430 (MH +).

Methyl {5- [1-hydroxy-3-oxo-2- (pyridin-2-ylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate, Trifluoroacetate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.46 (d, 1H), 7.88-7.80 (m, 2H), 7.64-7.56 (m, 3H) ), 7.46 (d, 1H), 7.40-7.35 (m, 2H), 7.30 (d, 1H), 7.06 (d, 1H), 4.53 (dd AB, 2H) ), 3.83 (s, 3H). MS about _{C 23 H 19 N 5 O 4} (EI): 412 (MH + -H 2 0).

Methyl {6- [2- (3,4-dichloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Yl} carbamate, acetate: ¹ H NMR (400 MHz, d ₆ -DMSO): 11.78 (br s, 3 H), 7.88 (d, 1 H), 7.81 (s, 1 H), 7. 69-7.60 (m, 2H), 7.51 (dd, 1H), 7.46 (s, 1H), 7.37 (tr, 1H), 7.32 (d, 1H), 7.26 (D, 1H), 6.93 (d, 1H), 3.73 (s, 3H), 1.91 (s, 3H). MS about _{C 23 H 15 Cl 2 FN 4} O 4 (EI) :( MH +).

  Methyl (5- {1-hydroxy-3-oxo-2-[(1R) -1-phenylethyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl ) Carbamate: The reported 1H NMR (400 MHz, d6-DMSO) is two ring-closed diastereomers and ring-opened isomers: 8.90 (d, 0.8H), 7.79-7. 77 (m, 1H), 7.71-7.76 (m, 2.6H), 7.61-7.59 (m, 2.6H), 7.53-7.51 (m, 2.6H) ), 7.48-7.45 (m, 3.6H), 7.42-7.36 (m, 2.2H), 7.27-7.10 (m, 9.2H), 7.00 -6.94 (m, 3.4H), 4.79-4.75 (m, 1H), 4.53-4.50 (m, 0.7 ), 4.42-4.39 (m, 0.7H), 3.82 (s, 2.1H), 3.81 (s, 2.1H), 3.78 (s, 3H), 3. 47-3.45 (m, 1H), 3.40-3.39 (m, 1H), 1.74 (d, 2.1H), 1.46 (d, 2.1H), 1.28 ( d, 3H); MS (EI) for C25H22N4O4: 443 (MH +).

Methyl (5- {1-hydroxy-3-oxo-2-[(1S) -1-phenylethyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl ) Carbamate: The reported ¹ H NMR (400 MHz, d ₆ -DMSO) is the two ring-closed diastereomers and ring-opening isomers: 8.94 (d, 0.6H), 7.82-7 .81 (m, 1H), 7.74-7.69 (m, 3.8H), 7.64-7.60 (m, 2.4H), 7.57-7.52 (m, 4.H). 2H), 7.51 (s, 0.9H), 7.48-7.43 (m, 0.3H), 7.42-7.39 (m, 0.8H), 7.30-7. 12 (m, 10.7H), 7.02-6.98 (m, 4.9H), 4.81-4.78m, 0.6H), 4 .55-4.49 (m, 0.7H), 4.44-4.38 (m, 1H), 3.83 (s, 3H), 3.82 (s, 2.3H), 3.79 (s, 2.8H), 1.74 ( d, 2.5H), 1.46 (d, 3H), 1.28 (s, 2.1H); C 25 H 22 N 4 O 4 relates MS ( EI): 443 (MH ^<+> ).

Methyl {5- [2- (5-ethynyl-2,4-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Il} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.86 (d, 1H) 7.71 (s, 1H), 7.62 (m, 3H), 7.41 (m, 2H) ), 7.33 (d, 1H) , 7.23 (d, 1H), 6.89 (d, 1H), 3.72 (s, 3H); C 25 H 16 N 4 O 4 F 2 for the MS (EI): 475 (MH ^<+> ).

Methyl {5- [2- (3-ethynyl-2,4-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Il} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.72 (s, 1H), 7.64 (m, 2H), 7.42 (m, 2H), 7.31 (d, 1H ), 7.25 (d, 1H), 7.19 (t, 1H), 6.91 (d, 1H), 3.73 (3H); C 25 H 16 MS regarding _{N 4 O 4 F 2 (EI} ): 475 (MH +).

Methyl {5- [2- (2-fluoro-3-prop-1-in-1-ylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.86 (d, 1H), 7.66 (s, 1H), 7.62 (m, 2H), 7.45 (broad s, 1H), 7.33 (m, 1H), 7.30 (d, 1H), 7.24 (d, 1H), 7.09 (t, 1H), 6.94 ( 1H), 3.73 (s, 3H ), 2.04 (s, 3H); C 26 H 19 N 4 O 4 F relates ^{MS (EI): 471 (MH} +).

Methyl (5- {1-hydroxy-2- [4- (methyloxy) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.82 (d, 1H), 7.57 (m, 4H), 7.27 (m, 4H), 7.00 (d, 1H), 6.81 (d, 2H), 3.75 (s, 3H), 3.67 (s, 3H); C 24 H 20 N 4 O 5 relating ^{MS (EI): 445 (MH} +).

Methyl {5- [2- (4-bromophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ 1 H NMR (400 MHz, d ₆ -DMSO): 7.86 (m, 2H), 7.58 (m 5H), 7.47 (m, 2H), 7.30 (m, 2H), 7.11 ( _{s, 1H), 3.79 (s} , 3H); C 23 H 17 N 4 O 4 Br relates ^{MS (EI): 494 (MH} +).

Methyl {5- [2- (4-chlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.86 (d, 2H), 7.61 (m, 5H), 7.32 (m, 4H), 7.11 (d, 1H), 3.79 ( _{s, 3H); C 23 H} 17 N 4 O 4 Cl about ^{MS (EI): 449 (MH} +).

Methyl {5- [2- (4-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ 1 H NMR (400 MHz, d ₆ -DMSO): 7.86 (d, 1H), 7.57 (m, 6H), 7.27 (d, 2H), 7.11 (m, 2H), 6.98 (m, 1H), 3.74 ( s, 3H); C 23 H 17 N 4 O 4 F relates ^{MS (EI): 434 (MH} +).

Methyl [5- (2-cyclohexyl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -1H-benzimidazol-2-yl] carbamate: ¹ H NMR (400 MHz, _{d 6 -DMSO): 7.69 (m} , 2H), 7.48 (m, 3H), 7.15 (m, 2H), 3.83 (s, 3H), 3.05 (t, 1H) , 2.20 (m, 2H), 1.76-1.49 (m, 2H), 1.27-0.85 (m, 6H); C 23 H 24 N 4 O 4 relates MS (EI): 421 (MH ^<+> ).

Methyl {5- [2- (2,5-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate : ¹ H NMR (400 MHz, d ₆ -DMSO): 11.62 (broad s, 1H), 7.87 (d, 1H), 7.72 (s, 1H), 7.63 (m, 2H), 7.47 (s, 1H), 7.32 (d, 1H), 7.20 (m, 4H), 6.93 (d, 1H), 3.73 (s, 3H); C 23 H 16 N ₄ O ₄ F ₂ relates ^{MS (EI): 451 (MH} +).

Methyl [5- (1-hydroxy-3-oxo-2- {2-[(trifluoromethyl) oxy] phenyl} -2,3-dihydro-1H-isoindol-1-yl) -1H-benzimidazole 2-yl] carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.02 (s, 1H), 7.89 (d, 1H), 7.71 (d, 2H), 7.62 (m , 4H), 7.42 (m, 2H), 7.29 (d, 1H), 7.23 (d, 1H), 7.10 (d, 1H), 3.83 (s, 3H); C MS about _{24 H 17 N 4 O 5 F} 3 (EI): 499 (MH +).

Methyl {5- [2- (2,3-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate : ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.74 (s, 1H), 7.63 (m, 2H), 7.45 (s, 1H), 7 .38-7.14 (m, 5H), 6.93 (d, 1H), 3.72 (s, 3H); C 23 H 16 N 4 O 4 F 2 relates MS (EI): 451 (MH + ).

Methyl {5- [2- (2,6-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate : ¹ H NMR (400 MHz, d ₆ -DMSO): 7.84 (d, 1H), 7.66 (m, 2H), 7.51 (s, 1H), 7.44-7.07 (m, 5H), 6.88-6.79 (m, 2H ), 3.75 (s, 0.6H) open-ring isomer, 3.70 (s, 2.4H) closed-ring _form; C _{23 H} 16 _N 4 O ₄ F ₂ on ^{MS (EI): 451 (MH} +).

Methyl {5- [2- (3-chloro-4-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 11.58 (broad s, 1H), 7.79 (d, 2H), 7.58 (m, 4H), 7.29 (m, 3H) ), 6.97 (s, 1H) , 3.72 (s, 3H); C 23 H 16 N 4 O 4 FCl relates ^{MS (EI): 466 (MH} +).

Methyl {5- [1-hydroxy-2- (3-iodophenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ 1 H NMR (400 MHz, d ₆ -DMSO): 8.06 (s, 1H), 7.84 (d, 1H), 7.73 (s, 1H), 7.52-7.63 (m, 5H) , 7.46 (d, 1H), 7.27 (d, 2H), 7.03 (m, 2H), 3.73 (s, 3H); C 23 H 17 N 4 O 4 relates MS (EI ): 541 (MH ⁺ ).

Methyl (5- {1-hydroxy-2- [3- (1-methylethyl) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2- Yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.81 (d, 1H), 7.67-7.56 (m, 4H), 7.35 (d, 2H), 7.27 (D, 2H), 7.17-7.10 (m, 2H), 6.99 (d, 1H), 3.79 (s, 3H), 2.74 (m, 1H), 1.10 ( d, 0.72H) open-ring isomer, 1.05 (d, 5.28H) closed-ring _{form; C 26 H 24 N 4 O} 4 relates ^{MS (EI): 457 (MH} +).
Methyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.88 (t, 2H), 7.67-7.61 (m, 2H), 7.56 (s, 1H), 7.48 ( m, 1H), 7.36 (m, 2H), 7.28 (d, 1H), 7.17 (t, 1H), 7.09 (d, 1H), 3.80 (s, 3H); _{C 23 H 16 N 4 O 4} ClF relates ^{MS (EI): 467 (MH} +).

Methyl {5- [2- (2-fluoro-3-iodophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.60-7.75 (m, 4H), 7.47 (s, 1H), 7.28 ( dd, 3H), 6.94 (t , 2H), 3.74 (s, 3H); C 23 H 16 N 4 O 4 FI relates ^{MS (EI): 558 (MH} +).

Methyl {6- [2- (5-ethynyl-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.91 (d, 1H), 7.83 (m, 1H), 7.74 (m, 1H), 7.64 (m, 1H) 7.37 (d, 2H), 7.03 (dd, 3H), 6.69 (d, 2H), 4.21 (s, 1H), 3.73 (s, 3H); C ₂₅ H ₁₇ N ₄ O ₄ F relates ^{MS (EI): 457 (MH} +).

Methyl {5- [2- (3-cyanophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ 1 H NMR (400 MHz, d ₆ -DMSO): 8.10 (s, 1H), 8.03 (s, 1H), 7.92 (dd, 2H), 7.61 (m, 4H), 7.50 (m, 1H), 7.37 ( d, 1H), 7.30 (d, 1H), 7.17 (d, 1H), 3.79 (s, 3H); C 24 H 17 N 5 O 4 MS (EI) for: 440 (MH ^<+> ).

Methyl [5- (2- {3-[(dimethylamino) methyl] phenyl} -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -1H-benzimidazole-2 -Yl "carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.86 (d, 1 H), 7.79 (s, 1 H), 7.68-7.54 (m, 5 H), 7. 38 (t, 1H), 7.31-7.21 (m, 3H), 6.97 (d, 1H), 4.18 (s, 2H), 3.74 (s, 3H), 2.50 _{(t, 6H); C 26} H 25 N 5 O 4 relates ^{MS (EI): 472 (MH} +).

Methyl {5- [2- (3-ethynyl-5-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.96 (s, 1H), 7.85 (d, 1H), 7.71 (s, 1H), 7.68 (s, 1H) 7.48-7.63 (m, 4H), 7.23-7.29 (m, 2H), 6.96 (dd, 1H), 3.77 (s, 0.6H) ring-opened product, 3.72 (s, 2.4H) closed-ring _{form, 2.28 (s, 3H);} C 26 H 20 N 4 O 4 relates ^{MS (EI): 453 (MH} +).

Methyl {5- [2- (cyclopropylmethyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate. ¹ H NMR (400 MHz, CD ₃ OD): 7.86 (s, 1H); 7.82-7.80 (m, 1H), 7.56-7.52 (m, 2H), 7.28 ( s, 1H), 7.27-7.25 (m, 1H), 3.93 (s, 1H), 3.13-2.98 (m, 2H), 0.96-0.91 (m, 1H), 0.35-0.21 (m, 3H ), 0.034-0.01 (m, 1H); C 21 H 20 N 4 O 4 relates ^{MS (EI): 393 (MH} +).

Methyl {5- [2- (2,2-dimethylpropyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate . ¹ H NMR (400 MHz, CD ₃ OD): 7.82-7.80 (m, 2H), 7.57-7.50 (m, 3H), 7.27-7.25 (m, 1H), 7.1 (br.s, 1H), 3.93 (s, 3H), 3.46 (d, J = 14 Hz, 1H), 2.54 (d, J = 14.4, 1H), 0. 92 (s, 7H), 0.78 (s, 2H); C 22 H 24 N 4 O 4 relates ^{MS (EI): 409 (MH} +).

Methyl {5- [2- (cyclohexylmethyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate. ¹ H NMR (400 MHz, CD ₃ OD): 7.85 (t, J = 6 Hz, 2H), 7.59-7.55 (m, 3H), 7.27 (dd, J ₁ = 17.6 Hz, _{J 2 = 6Hz, 2H),} 3.99 (s, 3H), 2.87 (q, J = 7.2Hz, 5H), 1.71-1.57 (m, 6H), 1.17-1 .07 (m, 3H), 0.96-0.91 (m, 2H); C 24 H 26 N 4 O 4 relates ^{MS (EI): 435 (MH} +).

Methyl {5- [1-hydroxy-2- (2-methylpropyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate. ¹ H NMR (400 MHz, CD ₃ OD): 7.86-7.83 (m, 2H), 7.59-7.54 (m, 3H), 7.25 (dd, J ₁ = 18.8 Hz, J ₂ = 6.8 Hz, 2H), 3.99 (s, 3H), 2.84 (q, J = 7.2 Hz, 5H), 1.90 (t, J = 7.2 Hz, 1H), 0 _{.88-0.82 (m, 6H); C} 21 H 22 N 4 O 4 relates ^{MS (EI): 395 (MH} +).

Methyl {5- [2- (cyclopentylmethyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate. ¹ H NMR (400 MHz, CD ₃ OD): 7.82-7.79 (m, 2H), 7.55-7.49 (m, 3H), 7.26-7.24 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 3.94 (s, 3H), 3.46 (q, J = 7.2 Hz, 1H), 2.96 (q, J = 7.6 Hz) , 1H), 2.14 (t, J = 7.2 Hz, 1H), 1.61 (br.s, 4H), 1.45 (br.s, 2H), 1.26-1.19 (m _{, 2H); C 23 H 24} N 4 O 4 relates ^{MS (EI): 421 (MH} +).

Methyl (2S) -cyclohexyl [1-hydroxy-1- (2-{[(methyloxy) carbonyl] amino} -1H-benzimidazol-5-yl) -3-oxo-1,3-dihydro-2H-iso Indol-2-yl] ethanoate. ¹ H NMR (400 MHz, CD ₃ OD): 7.85 (s, 1H), 7.78-7.76 (m, 1H), 7.69-7.65 (m, 3H), 7.54- 7.50 (m, 2H), 4.17 (d, J = 6.8 Hz, 1H), 3.90 (s, 3H), 3.65 (s, 3H), 1.69-1.45 ( m, 6H), 1.23-0.94 (m , 3H), 0.81-0.76 (m, 2H); C 26 H 28 N 4 O 6 relates ^{MS (EI): 493 (MH} +) .

Methyl (5- {1-hydroxy-2- [3- (1-methylethyl) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2- Il) Carbamate. ¹ H NMR (400 MHz, CD ₃ OD): 7.91 (d, J = 8 Hz, 1H), 7.76 (s, 1H), 7.65-7.61 (m, 2H), 7.45 ( d, J = 8.8 Hz, 1H), 7.33 (d, J = 6.8 Hz, 1H), 7.34-7.26 (m, 1H), 7.22 (s, 1H), 7. 19-7.14 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 3.92 (s, 3H), 2.77 (sep. J = 6.8 Hz, 1H), _{1.1 (t, J = 6.4Hz,} 6H); C 26 H 24 N 4 O 4 relates ^{MS (EI): 457 (MH} +).

Methyl {5- [2- (cyclobutylmethyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate. ¹ H NMR (400 MHz, CD ₃ OD): 7.79-7.77 (m, 2H), 7.53-7.48 (m, 3H), 7.22-7.20 (m, 2H), 3.90 (s, 3H), 3.55-3.50 (m, 1H), 3.12-3.05 (m, 1H), 2.53-2.44 (m, 1H), 1. 93-1.79 (m, 2H), 1.73 (s, 2H), 1.56 (s, 2H); C 22 H 22 N 4 O 4 relates ^{MS (EI): 407 (MH} +).

Methyl {5- [1-hydroxy-3-oxo-2- (tetrahydrofuran-2-ylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate. ¹ HNMR (400 MHz, CD ₃ OD): 7.84-7.81 (m, 2H), 7.57-7.52 (M, 3H), 7.26 (d, J = 6.8 Hz, 2H) 4.08 (t, J = 6.8 Hz, 1H), 3.95 (s, 3H), 3.92-3.61 (m, 3H), 3.05-2.99 (m, 1H) , 1.92-1.83 (m, 3H), 1.63 (s, 1H); C 22 H 22 N 4 O 5 relating ^{MS (EI): 405 (MH} +).

Methyl {5- [2- (5-bromo-2-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ): 7.89 (d, J = 7.2 Hz, 1H), 7.79-7.69 (m, 4H), 7.40 (d, J = 8. 8 Hz, 3H), 7.05 (s, 1H), 6.98 (d, J = 6.4 Hz, 1H), 3.83 (s, 3H), 1.49 (s, 3H); C ₂₄ H ₁₉ BrN ₄ O ₄ on ^{MS (EI): 509 (MH} +).

Methyl (5- {2- [5-chloro-2- (methyloxy) phenyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole- 2-yl) carbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ): 7.84 (d, J = 7.2 Hz, 1H), 7.66-7.60 (m, 3H), 7.41-7.39 (m, 2H), 7.16 (d, J = 8 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 3.40 (s, 3H); C ₂₄ H ₁₉ ClN ₄ O ₅ relating ^{MS (EI): 479 (MH} +).

Methyl (5- {2- [3- (1,1-dimethylethyl) phenyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole- 2-yl) carbamate. ¹ H NMR (400 MHz, CD ₃ OD): 7.91 (dd, J ₁ = 7.6 Hz, J ₂ = 2.0 Hz, ₁ H), 7.77 (s, 1 H), 7.46 (d, J _{= 8.4Hz, 1H), 7.34-7.33 (} m, 2H), 7.29 (dd, J 1 = 8.4Hz, J 2 = 1.6Hz, 1H), 7.20-7. 16 (m, 3H), 3.92 (s, 3H); C 27 H 26 N 4 O 4 relates ^{MS (EI): 471 (MH} +).

Methyl (5- {1-hydroxy-2- [5-methyl-2- (methyloxy) phenyl] 3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.59 (s, 1H), 7.88 (m, 1H) ring-opened body, 7.74 (d, 1H) ring-closed body, 7.66 (m, 1H), 7.57 (m, 2H), 7.48 (m, 1H), 7.43 (s, 1H) ring-closed body, 7.42 (s, 1H) ring-opened body, 7.26 (s, 1H) closed ring, 7.24 (s, 1H) open ring, 7.16 (m, 1H), 6.99 (m, 1H), 6.88 (s, 1H), 6.77 (d, 1H), 3.76 (s, 3H) ring-opened body, 3.71 (s, 3H) ring-closed body, 3.40 (s, 3H) ring-opened body, 3.35 (s, 3H) ring-closed body, 2. .16 (s, 3H) closed-ring form, 2.09 (s, 3H) ring open _{form; C 25 H 22 N 4 O} 5 relating ^{MS (EI): 459 (MH} +).

Methyl hydrochloride {5- [1-hydroxy-2- (3-methylphenyl) 3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ 1 H NMR (400 MHz, d ₆ -DMSO): 7.85 (d, 1H), 7.79 (br s, 1H), 7.68 (s, 1H), 7.64-7.56 (m, 2H) ), 7.44 (d, 1H), 7.38 (s, 1H), 7.26-7.21 (m, 3H), 7.15-7.11 (m, 1H), 6.95 ( d, 2H), 3.83 (s , 3H), 2.21 (s, 3H); C 24 H 20 N 4 O 4 relates ^{MS (EI): 429 (MH} +).

Methyl trifluoroacetate [5- (1-hydroxy-2-{[2- (methyloxy) phenyl] methyl} -3-oxo-2,3-dihydro-1H-isoindol-1-yl) -1H-benz Imidazol-2-yl] carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.76 (1H), 7.68 (br s, 1H), 7.49-7.40 (m, 3H), 7. 35-7.28 (m, 2H), 7.23 (d, 1H), 7.08-7.05 (m, 1H), 6.76-6.72 (m, 1H), 6.61 ( d, 1H), 4.64 (d , 1H), 4.29 (d, 1H), 3.90 (s, 3H), 3.66 (s, 3H); about _{C 25} H ₂₂ N 4 _{O 5} MS (EI): 459 (MH ^&lt; ^{+ &gt;} ).

Methyl trifluoroacetate [5- (1-hydroxy-2-{[3- (methyloxy) phenyl] methyl} -3-oxo-2,3-dihydro-1H-isoindol-1-yl) -1H-benz Imidazol-2-yl] carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.74 (1H), 7.67 (br s, 1H), 7.50-7.43 (m, 2H), 7. 43 (d, 1H), 7.24-7.20 (m, 2H), 6.93-6.90 (m, 1H), 6.65-6.60 (m, 2H), 6.53 ( d, 1H), 4.47 (d , 1H), 4.17 (d, 1H), 3.93 (s, 3H), 3.61 (s, 3H); about _{C 25} H ₂₂ N 4 _{O 5} MS (EI): 459 (MH ^&lt; ^{+ &gt;} ).

Methyl trifluoroacetate [5- (1-hydroxy-2-{[4- (methyloxy) phenyl] methyl} -3-oxo-2,3-dihydro-1H-isoindol-1-yl) -1H-benz Imidazole-2-yl] carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.75-7.70 (m, 2H), 7.51-7.44 (m, 2H), 7.39 (d, 1H), 7.24-7.20 (m, 2H), 7.00 (d, 2H), 6.51 (d, 2H), 4.47 (d, 1H), 4.17 (d, 1H) ), 3.92 (s, 3H) , 3.62 (s, 3H); C 25 H 22 N 4 O 5 relating ^{MS (EI): 459 (MH} +).

Methyl {5- [2- (3-bromophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ 1 H NMR (400 MHz, d ₆ -DMSO): 7.91 (s, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.63-7.52 (m, 4H) , 7.63-7.52 (m, 4H), 6.99 (s, 1H), 3.72 (s, 3H); C 23 H 17 N 4 O 4 relates MS (EI): 494 (MH + ).

Methyl trifluoroacetate {5- [2- (3-chlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate : ¹ H NMR (400 MHz, d ₆ -DMSO): 7.92 (br s, 1 H), 7.87 (d, 1 H), 7.77 (s, 1 H), 7.64-7.55 (m , 4H), 7.38 (d, 1H), 7.31-7.27 (m, 2H), 7.18 (d, 1H), 3.80 (s, 3H); C 23 H 17 ClN 4 O ₄ on ^{MS (EI): 449 (MH} +).

Methyl trifluoroacetate {5- [2- (3-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.92 (br s, 1H), 7.87 (d, 1H), 7.65-7.57 (m, 3H), 7.53- 7.47 (m, 2H), 7.38 (d, 1H), 7.33-7.27 (m, 2H), 7.18 (d, 1H), 6.98 (t, 1H), 3 _{.80 (s, 3H); C} 23 H 17 FN 4 O 4 relates ^{MS (EI): 433 (MH} +).

Methyl trifluoroacetate (5- {1-hydroxy-2- [3- (methyloxy) phenyl] methyl} -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole -2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.82 (d, 1H), 7.73 (br s, 1H), 7.60-7.53 (m, 3H) 7.34 (d, 1H), 7.23 (d, 1H), 7.16-7.11 (m, 4H), 6.70-6.66 (m, 1H), 3.78 (s) _{, 3H), 3.62 (s,} 3H); C 24 H 20 N 4 O 5 relating ^{MS (EI): 445 (MH} +).

Methyl trifluoroacetate {5- [2- (2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.84 (d, 1H), 7.72 (br s, 1H), 7.63-7.58 (m, 2H), 7.51 ( s, 1H), 7.15-7.10 (m, 4H), 7.15-7.10 (m, 2H), 7.03 (d, 1H), 3.77 (s, 3H); C ₂₃ H ₁₇ FN ₄ O ₄ relates ^{MS (EI): 433 (MH} +).

Methyl trifluoroacetate {5- [2- (2-chlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate : ¹ H NMR (400 MHz, d ₆ -DMSO): 7.85 (d, 1H), 7.75-7.62 (m, 3H), 7.56-7.51 (m, 1H), 7. 43-7.20 (m, 5H), 6.99 (d, 1H), 3.77 (s, 3H); C 23 H 17 ClN 4 O 4 relates ^{MS (EI): 449 (MH} +).

Methyl trifluoroacetate {5- [1-hydroxy-2- (2-methylphenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.85 (d, 1H), 7.75-7.62 (m, 3H), 7.56-7.51 (m, 1H), 7 .43-7.20 (m, 5H), 6.99 (d, 1H), 3.77 (s, 3H), 1.49 (s, 3H); C 23 H 17 ClN 4 O 4 relates MS ( EI): 449 (MH ^<+> ).

Methyl trifluoroacetate (5- {1-hydroxy-2- [2- (methyloxy) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.80 (d, 1H), 7.63-7.55 (m, 2H), 7.51 (s, 1H), 7. 46-7.42 (m, 1H), 7.31-7.17 (m, 4H), 7.10 (d, 2H), 6.88-6.83 (m, 2H), 3.79 ( _{s, 3H), 3.40 (s} , 3H); C 24 H 20 N 4 O 5 relating ^{MS (EI): 445 (MH} +).

Methyl trifluoroacetate {5- [1-hydroxy-2- (4-methylphenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.80 (d, 1H), 7.61 (br s, 1H), 7.58-7.53 (m, 3H), 7.33- 7.22 (m, 3H), 7.05-7.00 (m, 3H), 3.76 (s, 3H), 1.23 (s, 3H); C 24 H 20 N 4 O 4 for the MS (EI): 449 (MH ^<+> ).

Methyl trifluoroacetate (5- {1-hydroxy-3-oxo-2- [3- (trifluoromethyl) phenyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole- 2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.08 (s, 1H), 7.94 (s, 1H), 7.87-7.82 (m, 2H), 7 .64-7.55 (m, 3H), 7.50-7.42 (m, 2H), 7.34 (d, 1H), 7.27 (d, 1H), 7.14 (d, 1H) _{), 3.78 (s, 3H)} ; C 24 H 17 F 3 N 4 O 4 relates ^{MS (EI): 483 (MH} +).

Methyl {5- [2- (3,5-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate : ¹ H NMR (400 MHz, d ₆ -DMSO): 7.93 (s, 1H), 7.86 (s, 1H), 7.70-7.43 (m, 7H), 7.31-7. 26 (m, 2H), 7.04-6.89 (m, 2H), 3.73 (s, 3H); C 23 H 16 F 2 N 4 O 4 relates ^{MS (EI): 451 (MH} +) .

Methyl trifluoroacetate {5- [2- (3-{[2- (dimethylamino) ethyl] oxy} phenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl ] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.81 (d, 1H), 7.72 (s, 1H), 7.61-7.53 (M, 3H), 7.30-7.28 (m, 2H), 7.25 (d, 1H), 7.18-7.14 (m, 2H), 7.05 (d, 1H), 6.77-6.74 (m, 1H), 4.18 (t, 2H), 3.76 (s, 3H), 3.45 (t, 2H), 2.81 (s, 6H); C ₂₇ H ₂₇ N ₅ O ₅ relating ^{MS (EI): 502 (MH} +).

Methyl trifluoroacetate {5- [1-hydroxy-3-oxo-2- (1,3-thiazol-2-ylmethyl] -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole -2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.79 (d, 1H), 7.60-7.53 (m, 4H), 7.49 (s, 1H), 7.32 (d, 1H), 7.25 (d, 1H), 6.97 (d, 1H), 4.78 (d, 1H), 4.50 (d, 1H), 3.80 (s _{, 3H); C 21 H 17} N 5 O 4 S about ^{MS (EI): 418 (MH} +).

Methyl trifluoroacetate {5- [2- (3,4-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.79 (br s, 1 H), 7.58 (d, 1 H), 7.54-7.49 (m, 1 H), 7.42 − 7.36 (m, 3H), 7.24-7.18 (m, 3H), 6.88-6.81 (m, 1H), 3.88 (s, 3H); C 23 H 16 F 2 MS on the _{N 4 O 4 (EI):} 451 (MH +).

Methyl (5- {2- [1- (3,5-difluorophenyl) ethyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole- 2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.92 (d, 0.33H), 7.81-7.79 (m, 0.33H), 7.70-7. 49 (m, 4H), 7.41-7.13 (m, 4H), 7.05-6.80 (m, 3H), 6.61-6.55 (1H), 4.82 (q, 0.33H), 4.56 (q, 0.33H), 4.40 (q, 0.33H), 3.77-3.69 (m, 3H), 1.73 (d, 1H), 1 .43 (d, 1H), 1.30 (d, 1H); C 25 H 20 F 2 N 4 O 4 relates MS (EI): 79 ^(MH +).

Methyl (5- {2- [1- (3-fluorophenyl) ethyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2- Yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.89 (d, 0.33H), 7.79-7.77 (m, 0.33H), 7.68-7.57 ( m, 3H), 7.54-7.48 (m, 1H), 7.32-7.18 (m, 3H), 7.14-6.92 (m, 3H), 6.85-6. 71 (m, 1H), 4.82 (q, 0.33H), 4.55 (q, 0.33H), 4.41 (q, 0.33H), 3.75-3.71 (m, 3H), 1.74 (d, 1H ), 1.44 (d, 1H), 1.29 (d, 1H); C 25 H 21 FN 4 ₄ about the ^{MS (EI): 461 (MH} +).

Methyl (5- {2- [1- (5-chloro-2-methylphenyl) ethyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benz Imidazol-2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.92 (d, 0.5H), 8.01-7.97 (m, 0.5H), 7.78- 7.75 (m, 1H), 7.64-7.50 (m, 2H), 7.43-7.27 (m, 4H), 7.15-7.06 (m, 2H), 6. 98-6.91 (m, 1H), 4.98 (q, 0.5H), 4.82 (q, 0.25H), 4.51 (q, 0.25H), 3.76-3. 72 (m, 3H), 2.19 (s, 1H), 2.14 (s, 2H), 1.66 (d, 0.5H), 1.55 (d, _{.5H), 1.24 (d, 2H} ); C 26 H 23 ClN 4 O 4 relates ^{MS (EI): 461 (MH} +).

Methyl {5- [1-hydroxy-2- (3-{[2- (methyloxy) ethyl] oxy} phenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H -Benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.82 (d, 1H), 7.62-7.49 (m, 4H), 7.27-7. 23 (m, 2H), 7.18-7.11 (m, 3H), 6.99 (d, 1H), 6.69-6.67 (m, 1H), 3.93 (t, 2H) , 3.73 (s, 3H), 3.56 (t, 2H), 3.25 (s, 3H); C 26 H 24 N 4 O 6 relates ^{MS (EI): 489 (MH} +).

Methyl {5- [2- (3-bromo-4-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.94 (d, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.64-7.51 ( m, 4H), 7.32-7.25 (m , 3H), 6.98 (d, 1H), 3.73 (s, 3H); C 23 H 16 BrFN 4 O 4 relates MS (EI): 512 (MH ⁺ ).

Methyl (5- {2- [3- (aminocarbonyl) phenyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.17 (s, 1H), 7.88 (s, 1H), 7.84 (d, 1H), 7.67 (s, 1H), 7.62-7.50 (m, 5H), 7.33-7.21 (m, 4H), 6.96 (d, 1H), 3.72 (s, 3H), 2.54 (s, _{2H); C 24 H 19 N} 5 O 5 relating ^{MS (EI): 458 (MH} +).

Methyl (5- {1-hydroxy-2- [3- (methylsulfonyl) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.37 (s, 1H), 7.90-7.85 (m, 3H), 7.69-7.50 (m, 5H), 7 .30 (d, 1H), 7.25 (d, 1H), 7.00 (d, 1H), 3.72 (s, 3H), 3.08 (s, 3H); C ₂₄ H ₂₀ N ₄ O ₆ S about ^{MS (EI): 493 (MH} +).

Methyl (5- {1-hydroxy-3-oxo-2- [3- (phenyloxy) phenyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.79 (d, 1H), 7.61-7.50 (m, 3H), 7.45 (br s, 1H), 7.39 ( d, 1H), 7.28-7.20 (m, 6H), 7.08-7.03 (m, 1H), 6.90 (d, 1H), 6.77 (d, 1H), 6 .71 (d, 1H), 3.72 (s, 3H); C 29 H 22 N 4 O 5 relating ^{MS (EI): 507 (MH} +).

Methyl trifluoroacetate [5- (1-hydroxy-3-oxo-2- {3-[(phenylmethyl) oxy] phenyl} -2,3-dihydro-1H-isoindol-1-yl) -1H-benz Imidazol-2-yl] carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.84 (d, 1H), 7.75 (s, 1H), 7.63-7.55 (m, 3H) 7.38-7.35 (m, 6H), 7.27-7.25 (m, 2H), 7.16-7.12 (m, 3H), 6.79-6.76 (m, 1H), 4.95 (s, 2H ), 3.79 (s, 3H); C 30 H 24 N 4 O 5 relating ^{MS (EI): 521 (MH} +).

Methyl [5- (2-biphenyl-3-yl-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -1H-benzimidazol-2-yl] carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.83 (d, 1H), 7.78 (s, 1H), 7.66-7.47 (m, 5H), 7.44-7.24 (m , 8H), 7.01 (d, 1H), 6.54 (s, 1H), 3.71 (s, 3H); C 29 H 22 N 4 O 4 relates ^{MS (EI): 491 (MH} +) .

Methyl {5- [2- (4-fluoro-3-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.80 (d, 1H), 7.60-7.52 (m, 3H), 7.46 (br s, 1H), 7.39 (d, 1H), 7.02-6.97 ( m, 1H), 6.92 (d, 1H), 3.71 (s, 3H), 2.11 (s, 3H); C 24 H 19 MS on _{FN 4 O 4 (EI):} 447 (MH +).

Methyl hydrochloride {5- [2- (5-bromo-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.92-7.87 (m, 2H), 7.72-7.58 (m, 4H), 7.55-7.50 ( m, 1H), 7.41 (d, 1H), 7.32 (d, 1H), 7.22-7.18 (m, 1H), 7.12 (d, 1H), 3.82 (s) _{, 3H); C 23 H 16} BrFN 4 O 4 relates ^{MS (EI): 512 (MH} +).

Methyl (5- {2- [3- (acetylamino) phenyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 9.88 (s, 1H), 7.88-7.78 (m, 2H), 7.63-7.40 (m, 5H), 7 .25-7.05 (m, 4H), 6.92 (d, 1H), 3.73 (s, 3H), 1.98 (s, 3H); C 25 H 21 N 5 O 5 related to MS ( EI): 472 (MH ^<+> ).

Methyl hydrochloride (5- {1-hydroxy-3-oxo-2- [3- (phenylmethyl) phenyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl ) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.81 (d, 1H), 7.68 (br s, 1H), 7.60-7.53 (m, 3H), 7.33 -7.29 (m, 3H), 7.23 (d, 1H), 7.17-7.06 (m, 5H), 6.97-6.94 (m, 2H), 3.79 (s _{, 3H), 3.77 (s,} 2H); C 30 H 24 N 4 O 4: relates ^{MS (EI) 505 (MH +} ).

Methyl (5- {2- [3- (aminosulfonyl) phenyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.34 (s, 1H), 7.86 (d, 1H), 7.79 (s, 1H), 7.70-7.39 (m , 9H), 7.29-7.23 (m, 2H), 6.99 (d, 1H), 3.72 (s, 3H); C 23 H 19 N 5 O 6 S about MS (EI): 494 (MH ^<+> ).

Methyl {5- [2- (3-acetylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ 1 H NMR (400 MHz, d ₆ -DMSO): 8.22 (s, 1H), 7.86 (d, 1H), 7.79 (d, 1H), 7.73-7.69 (m, 2H) 7.64-7.48 (m, 3H), 7.42-7.38 (m, 1H), 7.29 (d, 1H), 7.26 (d, 1H), 6.99 (d , 1H), 3.73 (s, 3H), 2.46 (s, 3H); C 25 H 20 N 4 O 5 relating ^{MS (EI): 457 (MH} +).

Methyl (5- {1-hydroxy-3-oxo-2- [3- (phenylamino) phenyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl) Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.14 (s, 1H), 7.81 (d, 1H), 7.62-7.52 (m, 4H), 7.30-7 .22 (m, 3H), 7.15-6.95 (m, 5H), 6.80-6.72 (m, 4H), 3.73 (s, 3H); C 29 H 23 N 5 O MS (EI) for ₄ : 506 (MH ^<+> ).

Methyl trifluoroacetate (5- {2- [3- (dimethylamino) phenyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.89 (d, 1 H), 7.72 (s, 1 H), 7.68-7.59 (m, 2 H), 7. 48 (d, 1H), 7.28-7.25 (m, 2H), 7.18-7.14 (m, 1H), 7.08 (s, 1H), 6.92 (d, 1H) , 6.74 (d, 1H), 3.84 (s, 3H), 2.84 (s, 6H); C 25 H 23 N 5 O 4 relates ^{MS (EI): 458 (MH} +).

Methyl trifluoroacetate [5-({2-[(2-phenylhydrazino) carbonyl] phenyl} carbonyl) -1H-benzimidazol-2-yl] carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8 .56 (d, 1H), 8.35-8.31 (m, 1H), 8.15-8.11 (m, 1H), 7.75 (d, 1H), 7.65-7.60 (m, 3H), 7.46 ( d, 1H), 7.41-7.35 (m, 3H), 7.26 (d, 1H), 3.78 (s, 3H); C 23 H 19 MS on the _{N 5 O 4 (EI):} 430 (MH +).

Methyl trifluoroacetate {5-[(2-{[(phenyloxy) amino] carbonyl} phenyl) carbonyl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7 .87 (d, 1H), 7.83 (br s, 1H), 7.74-7.70 (m, 1H), 7.66-7.62 (m, 1H), 7.57 (s, 1H), 7.45-7.40 (m, 2H), 7.30-7.25 (m, 2H), 7.14-7.10 (m, 3H), 7.04-7.00 ( _{m, 1H), 3.80 (s} , 3H); C 23 H 18 N 4 O 5 relating ^{MS (EI): 431 (MH} +).

Methyl trifluoroacetate {5- [1-hydroxy-3-oxo-2- (pyrrolidin-2-ylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.88 (br s, 1 H), 8.34 (br s, 1 H), 7.78 (d, 1 H), 7.62-7. 53 (m, 3H), 7.44-7.36 (m, 2H), 7.28 (d, 1H), 7.12-6.99 (m, 1H), 3.79 (s, 3H) 3.73-3.70 (m, 1H), 3.62-3.50 (m, 1H), 3.24-3.11 (m, 2H), 1.99-1.85 (m, 2H), 1.80-1.75 (m, 1H ), 1.70-1.60 (m, 1H); C 22 H 23 ₅ O ₄ on ^{MS (EI): 422 (MH} +).

Methyl trifluoroacetate {5- [1-hydroxy-3-oxo-2- (pyrrolidin-3-ylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.68 (br s, 2H), 7.76 (d, 1H), 7.59-7.51 (m, 3H), 7.41 (D, 1H), 7.27-7.23 (m, 2H), 6.99 (d, 1H), 3.79 (s, 3H), 3.58-3.48 (m, 1H), 3.22-3.17 (m, 2H), 3.08-3.00 (m, 1H), 2.96-2.82 (m, 2H), 1.97-1.85 (m, 1H) _{), 1.68-1.51 (m, 1H)} ; C 22 H 23 N 5 O 4 relates MS (EI): 422 (MH ⁺ ).

Methyl hydrochloride {5- [2- (5-chloro-3-ethynyl-2-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benz Imidazole-2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.91 (d, 1H), 7.85-7.65 (m, 4H), 7.52-7.48 ( m, 1H), 7.45-7.34 (m, 3H), 6.97 (d, 1H), 4.50 (s, 1H), 3.82 (s, 3H), 1.57 (s) _{, 3H); C 26 H 19} ClN 4 O 4 relates ^{MS (EI): 486 (MH} +).

Methyl {5- [2- (5-chloro-3-iodo-2-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole -2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.91-7.87 (m, 2H), 7.80-7.63 (m, 4H), 7.46-7 .41 (m, 1H), 7.34-7.28 (m, 2H), 6.87 (d, 1H), 3.78 (s, 3H), 1.55 (s, 3H); C ₂₄ MS regarding _{H 18 ClIN 4 O 4 (EI} ): 589 (MH +).

Methyl hydrochloride {5- [2- (3-ethyl-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.78 (br s, 1H), 7.68-7.58 (m, 3H), 7. 41 (d, 1H), 7.30 (d, 1H), 7.21-7.04 (m, 3H), 7.07-7.02 (m, 1H), 3.83 (s, 3H) , 2.50 (q, 2H), 1.02 (t, 3H); C 25 H 21 FN 4 O 4 relates ^{MS (EI): 461 (MH} +).

Methyl hydrochloride {5- [2- (3-ethenyl-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.90-7.87 (m, 2H), 7.71-7.60 (m, 3H), 7.58-7.54 ( m, 1H), 7.43 (d, 1H), 7.30-7.25 (m, 2H), 7.20-7.10 (m, 2H), 6.71 (dd, 1H), 5 .86 (d, 1H), 5.39 (d, 1H), 3.83 (s, 3H); C 25 H 19 FN 4 O 4 relates ^{MS (EI): 459 (MH} +).

Methyl hydrochloride {5- [2- (2-fluoro-5-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.83 (s, 1H), 7.68-7.60 (m, 3H), 7.44 (D, 1H), 7.30 (d, 1H), 7.24 (d, 1H), 7.16 (d, 1H), 7.12-7.08 (m, 1H), 7.04- 6.99 (m, 1H), 3.84 (s, 3H), 2.22 (s, 3H); C 24 H 19 FN 4 O 4 relates ^{MS (EI): 447 (MH} +).

Methyl hydrochloride (5- {2- [2-fluoro-5- (methyloxy) phenyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole -2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.88-7.67 (m, 2H), 7.69-7.61 (m, 3H), 7.44 (d , 1H), 7.30 (d, 1H), 7.16 (d, 1H), 7.11-7.06 (m, 1H), 6.95-6.93 (m, 1H), 6. 88-6.84 (m, 1H), 3.84 (s, 3H), 3.64 (s, 3H); C 24 H 19 FN 4 O 5 relating ^{MS (EI): 463 (MH} +).

Methyl trifluoroacetate (6- {2-[(3-fluorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.84-7.70 (m, 2H), 7.55-7.46 (m, 2H), 7.39-7.30 (m , 1H), 7.26-7.11 (m, 2H), 7.07-7.00 (m, 1H), 6.91 (d, 1H), 6.83-6.73 (m, 2H) ), 4.55 (d, 1H) , 4.22 (d, 1H), 3.95 (s, 3H); C 24 H 19 FN 4 O 4 relates ^{MS (EI): 447 (MH} +).

Methyl trifluoroacetate (6- {2-[(4-fluorophenyl) methyl] -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.86-7.70 (m, 2H), 7.55-7.47 (m, 2H), 7.41-7.34 (m , 1H), 7.25-7.11 (m, 4H), 6.78 (t, 2H), 4.57 (d, 1H), 4.20 (d, 1H), 3.96 (s, _{3H); C 24 H 19 FN} 4 O 4 relates ^{MS (EI): 447 (MH} +).

Methyl trifluoroacetate (5- {1-hydroxy-2-[(3-iodophenyl) methyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2 -Yl) carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.86-7.60 (m, 2H), 7.56-7.49 (m, 2H), 7.35 (d, 1H), 7.32-7.20 (m, 3H), 7.12-7.05 (m, 2H), 6.83 (t, 1H), 4.38 (d, 1H), 4.29 (d, _{1H), 3.97 (s, 3H} ); C 24 H 19 IN 4 O 4 relates ^{MS (EI): 555 (MH} +).

Methyl trifluoroacetate {6- [2- (3-amino-5-chlorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.83 (d, 1H), 7.77 (br s, 1H), 7.64-7.53 (m, 3H), 7 .39 (d, 1H), 7.23 (d, 1H), 7.14 (d, 1H), 6.84 (t, 1H), 6.79 (t, 1H), 6.35 (t, 1H), 6.29-6.27 (m, 1H ), 6.22-6.19 (m, 1H), 3.81 (s, 3H); C 23 H 18 ClN 5 O 4 relates MS (EI ): 464 (MH ⁺ ).

Methyl hydrochloride {5- [2- (3-ethynyl-4-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.96 (brs, 1H), 7.88 (d, 1H), 7.74-7.68 (m, 2H), 7. 67-7.53 (m, 3H), 7.45 (d, 1H), 7.31-7.14 (m, 3H), 4.54 (s, 1H), 3.84 (s, 3H) _{; C 25 H 17 FN 4 O} 4 relates ^{MS (EI): 457 (MH} +).

Methyl [5- (1-hydroxy-3-oxo-2-pyrrolidin-3-yl-2,3-dihydro-1H-isoindol-1-yl) -1H-benzimidazol-2-yl] carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.73 (d, 1H), 8.30 (dd, 1H), 7.95-7.85 (m, 2H), 7.77 (s, 1H), 7.72-7.48 (m, 3H), 7.35-7.28 (m, 2H), 7.26 (d, 1H), 6.99 (d, 1H), 3.72 (s, _{3H); C 22 H 17 N} 5 O 4 relates ^{MS (EI): 416 (MH} +), 438 (MNa +).

Methyl hydrochloride {5- [2- (3-bromo-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.93 (br s, 1H), 7.91-7.87 (m, 1H), 7.71-7.57 (m, 4H) ), 7.45-7.35 (m, 2H) , 7.30 (d, 1H), 7.16-7.09 (m, 2H), 3.82 (s, 3H); C 23 H 16 MS ^(EI) on _{BrFN 4 O 4: 511 (MH} +), 533 (MNa +).

Methyl hydrochloride {5- [2- (3-chloro-2,4-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.98 (br s, 1H), 7.93-7.89 (m, 1H), 7.73-7.62 (m , 2H), 7.60 (br s , 1H), 7.47-7.30 (m, 4H), 7.14 (d, 1H), 3.83 (s, 3H); C 23 H 15 ClF MS ^(EI) about _{2 N 4 O 4: 485 (} MH +), 507 (MNa +).

Methyl hydrochloride {5- [2- (5-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.97 (brs, 1H), 7.91-7.88 (m, 1H), 7.72-7.62 (m, 3H) ), 7.51 (dd, 1H), 7.45 (d, 1H), 7.44-7.38 (m, 1H), 7.33 (d, 1H), 7.26 (t, 1H) , 7.15 (d, 1H), 3.83 (s, 3H); C 23 H 16 ClFN 4 O 4 relates ^{MS (EI): 467 (MH} +).

Methyl trifluoroacetate {5- [1-hydroxy-3-oxo-2- (phenylsulfonyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.92-7.17 (m, 13H), 3.82 (s, 3H); MS (EI) for C ₂₃ H ₁₈ N ₄ O ₆ S: 479 (MH ⁺ ).
Methyl hydrochloride {5- [2- (3-bromo-2,5-difluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.04 (br s, 1H), 7.91 (d, 1H), 7.77-7.58 (m, 4H), 7.45 (d, 1H), 7.35-7.24 (m, 2H), 7.16 (d, 1H), 3.83 (s, 3H); C 23 H 15 BrF 2 N 4 O 4 MS (EI) for: 529 (MH ^<+> ).

Methyl hydrochloride (5- {1-hydroxy-2- [2-methyl-5- (methyloxy) phenyl] -3-oxo-2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole -2-yl) carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.88 (d, 1H), 7.80-6.70 (m, 10H), 3.85 (s, 3H), 3.72 (s, 2H), 3.24 (s, 1H), 2.16 (s, 1H), 1.43 (s, 2H); C 25 H 22 N 4 O 5 relating MS (EI): 459 (MH ⁺ ).

Example 15: 3- [2-Amino-1- (1,1-dimethylethyl) -1H-benzimidazol-5-yl] -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H -Isoindol-1-one: 2-({4-[(1,1-dimethylethyl) amino] -3-nitrophenyl} carbonyl) benzoic acid (1.5 g, 4.38 mmol), HOAt (0 in DMF 0.5M, 13.14 mL, 6.57 mmol), N-methylmorpholine (1.93 mL, 17.5 mmol) and HATU (2.16 g, 5.69 mmol) in a solution of benzylamine (718 uL, 6.57 mmol). In addition, the reaction mixture was stirred at 60 ^° C. for 16 hours. The mixture was cooled to room temperature and the solvent was evaporated. The pale yellow precipitate was filtered and rinsed with a mixture of acetonitrile-ethyl acetate (1: 5, 200 mL). The filtrate was washed with water and brine, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude 3- {4-[(1,1-dimethylethyl) amino] -3-nitrophenyl} -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindole-1- On (1.8 g, 95%) was used without further purification. C ₂₅ H ₂₅ N ₃ O ₄ relates ^{MS (EI): 454 (MNa} +).

3- {4-[(1,1-dimethylethyl) amino] -3-nitrophenyl} -3-hydroxy-2- (phenylmethyl) -2 in a mixed solution of tetrahydrofuran-ethyl acetate (1: 1, 20 mL) , 3-Dihydro-1H-isoindol-1-one (1.8 mg, 4.17 mmol) was hydrogenated with 10% Pd—C (50 mg) at 40 psi for 18 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO _2, hexanes / ethyl acetate) to give 3- {3-amino-4 - [(1,1-dimethylethyl) amino] phenyl} -3-hydroxy-2- (phenylmethyl ) -2,3-dihydro-1H-isoindol-1-one (950 mg, 57%) was obtained. C ₂₅ H ₂₇ N ₃ O ₂ relates ^{MS (EI): 402 (MH} +).

3- {3-amino-4-[(1,1-dimethylethyl) amino] phenyl} -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one (347 mg , 0.862 mmol) and cyanogen bromide (100 mg, 0.948 mmol) in absolute ethanol (10 mL) was heated to reflux for 6 hours, at which time it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC to give 3- [2-amino-1- (1,1-dimethylethyl) -1H-benzimidazol-5-yl] -3-hydroxy-2- (phenylmethyl) -2, 3-Dihydro-1H-isoindol-1-one (2.7 mg) was obtained. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.61 (d, 1H), 7.56-7.53 (m, 2H), 7.32 (br s, 1H), 7.30 (d, 1H), 7.09-7.07 (m, 5H), 6.92 (d, 1H), 4.41 (d, 1H), 4.22 (d, 1H) _{), 1.73 (s, 9H)} ; C 26 H 26 N 4 O 2 relates ^{MS (EI): 427 (MH} +).

Example 16: 3- (2-Amino-1H-benzimidazol-5-yl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one: 3- ( 3,4-Diaminophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one (613 mg, 1.77 mmol) and cyanogen bromide (188 mg, 1.77 mmol) ) In absolute ethanol (10 mL) was heated at 60 ^° C. for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC. To the combined fractions, 6N hydrochloric acid (10 mL) was added and heated for 10 hours, at which point saturated aqueous sodium bicarbonate was added until pH 7 was reached. To this aqueous layer, ethyl acetate (300 mL) was added and then separated. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give 3- (2-amino-1H-benzimidazol-5-yl) -3-hydroxy-2- (phenylmethyl). ) -2,3-dihydro-1H-isoindol-1-one (10.3 mg) was obtained. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.59-7.52 (m, 2H), 7.26-7.18 (m, 3H), 7.12 -7.09 (m, 5H), 7.03-7.01 (m, 1H), 4.43 (d, 1H), 4.21 (d, 1H), 3.48-3.39 (m _{, 1H); C 22 H 18} N 4 O 2 relates ^{MS (EI): 371 (MH} +).

Example 17: Methyl {6- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1-methyl-1H-benzimidazole-2 -Il} carbamate: methyl 2-[(4-amino-3-nitrophenyl) carbonyl] benzoate (0.74 g, 2.47 mmol) was dissolved in acetic acid (9 mL) at 45 ° C. to prepare tin (II) chloride Hydrate (2.22 g, 9.84 mmol) was added. The mixture was stirred at 75 ° C. for 7 hours and then concentrated under reduced pressure. The residue was transferred to an Erlenmeyer flask with a small amount of ethyl acetate and diluted with ether (20 mL). The mixture was stirred while cooling in an ice-water bath, and sodium hydroxide (50% aqueous solution) (6 mL) was added dropwise. The formed solid was removed by filtration and washed with hot ethyl acetate. The filtrates were combined and concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give methyl 2-[(3,4-diaminophenyl) carbonyl] benzoate as a yellow solid (0.245 g, 0.907 mmol, 37 % Yield). ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (dd, 1H), 7.65 (td, 1H), 7.57 (td, 1H), 7.32 (dd, 1H), 6. 93 (d, 1H), 6.66 (dd, 1H), 6.44 (d, 1H), 5.49 (s, 2H), 4.69 (s, 2H), 3.57 (s, 3H) _{); C 15 H 14 N 2} O 3 about ^{MS (EI): 293 (MNa} +).

Methyl 2-[(3,4-diaminophenyl) carbonyl] benzoate (0.215 g, 0.796 mmol) was dissolved in N, N-dimethylformamide (3 mL) and di-tert-butyl dicarbonate (0.208 g). 0.954 mmol) was added. The mixture was stirred at room temperature for 15 hours. The mixture was partitioned between ethyl acetate and lithium chloride (5% aqueous solution). The organic portion was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil that was purified by column chromatography (ethyl acetate-hexanes 1: 1). Methyl 2-{[4-amino-3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) phenyl] carbonyl} benzoate in a yellow foam (0.245 g, 0.662 mmol, 76% yield). ). ¹ H NMR (400 MHz, d ₆ -DMSO): 8.33 (br s, 1H), 7.90 (dd, 1H), 7.71-7.56 (m, 3H), 7.34 (dd, 1H), 7.10-7.02 (m, 1H), 6.63 (d, 1H), 5.88 (s, 2H), 3.60 (s, 3H), 1.43 (s, 9H) _{); C 20 H 22 N 2} O 5 related to ^{MS (EI): 393 (MNa} +).

Methyl 2-{[4-amino-3-({[(1,1-dimethylethyl) oxy] carbonyl} amino) phenyl] carbonyl} benzoate (0.217 g, 0.586 mmol) was dissolved in tetrahydrofuran (3 mL). And cooled in an ice bath. Sodium hydride (60 wt% dispersion in oil; 0.024 g, 0.600 mmol) was added followed by iodomethane (0.037 mL, 0.594 mmol) dropwise. The mixture was stirred for 1.1 hours before iodomethane (0.100 mL, 1.61 mmol) was added dropwise. The mixture was stirred for an additional hour before sodium hydride (60 wt% dispersion in oil; 0.019 g, 0.475 mmol) was added and the mixture was stirred for an additional 0.25 hour. The mixture was quenched with 1N hydrochloric acid. The aqueous layer portion was extracted with ethyl acetate (2x). The organic portions were combined and washed with saturated sodium bicarbonate solution. The ethyl acetate portion was dried over sodium sulfate, filtered, and concentrated in vacuo to give a 4: 1 mixture (0.115 g) of mono-N-methylated material: di-N-methylated material. The aqueous layer portion was acidified with 1N hydrochloric acid and extracted with ethyl acetate (2x). The organic portion was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 2-({4-amino-3-[{[(1,1-dimethylethyl) oxy] carbonyl} (methyl ) Amino] phenyl} carbonyl) benzoic acid as an orange oil which was dissolved in methanol (0.5 mL) and toluene (4.5 mL), cooled in an ice bath and (trimethylsilyl) diazomethane (2 in hexanes). .0M solution; 0.200 mL, 0.400 mmol). The mixture was stirred for 0.1 hour, then quenched with 0.5N hydrochloric acid and partitioned with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow foam (0.120 g). This yellow foam is combined with a 4: 1 mixture of the isolated mono- and di-methylated materials (0.115 g) and purified by column chromatography (ethyl acetate-hexanes 1: 1). Methyl 2-({4-amino-3-[{[(1,1-dimethylethyl) oxy] carbonyl} (methyl) amino] phenyl} carbonyl) benzoate in yellow form (0.167 g, 0.435 mmol, 74 % Yield). ¹ H NMR (400 MHz, CDCl ₃ ): 8.02 (dd, 1H), 7.65-7.30 (m, 5H), 6.69 (d, 1H), 4.24 (s, 2H), 3.65 (s, 3H), 3.13 (s, 3H), 1.56 (s, 9H); C 21 H 24 N 2 O 5 related to ^{MS (EI): 407 (MNa} +).

Methyl 2-({4-amino-3-[{[(1,1-dimethylethyl) oxy] carbonyl} (methyl) amino] phenyl} carbonyl) benzoate (0.167 g, 0.435 mmol) was added to dichloromethane (1 mL ) And treated with trifluoroacetic acid (0.7 mL) in 1.5 hours. This mixture was adjusted to a pH of about 8 by the addition of saturated sodium bicarbonate solution. The aqueous layer portion was partitioned between ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an orange foam which was dissolved in N, N-dimethylformamide (1 mL) and methyl isothiocyanate carbamate (0. 120 mL, 1.026 mmol). After 1 hour, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.120 g, 0.625 mmol) was added and the mixture was stirred at 65 ° C. for 0.5 hour. The mixture was partitioned between ethyl acetate and lithium chloride (5% aqueous solution). The organic portion was washed with 0.5N hydrochloric acid, saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil which was purified by column chromatography (ethyl acetate-hexanes 4: 1) purify methyl 2-[(1-methyl-2-{[(methyloxy) carbonyl] amino} -1H-benzimidazol-6-yl) carbonyl] benzoate as a colorless film (0.049 g; 134 mmol, 31% yield). ¹ H NMR (400 MHz, CDCl ₃ ): 11.4 (s, 1H), 8.06 (dd, 1H), 7.81 (d, 1H), 7.65 (td, 1H), 7.57 ( td, 1H), 7.42 (dd, 1H), 7.39 (dd, 1H), 7.19 (d, 1H), 3.78 (s, 3H), 3.67 (s, 3H), _{3.61 (s, 3H); C} 19 H 17 N 3 O 5 relating ^{MS (EI): 368 (MH} +).

Methyl 2-[(1-methyl-2-{[(methyloxy) carbonyl] amino} -1H-benzimidazol-6-yl) carbonyl] benzoate (0.049 g, 0.134 mmol) was added to tetrahydrofuran / methanol (1: 1, 1 mL) and 4N potassium hydroxide (0.250 mL, 1.00 mmol) was added. The mixture was stirred for 0.5 h before methanol (0.5 mL) and 4N potassium hydroxide (0.250 mL, 1.00 mmol) were added. The mixture was stirred for 1.1 hours and then concentrated under reduced pressure. The residue was partitioned between ether and water. The aqueous layer was acidified with 1N hydrochloric acid to a pH of about 1-2, then extracted with ethyl acetate (2x). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a colorless solid (0.027 g, 0.076 mmol) that was dissolved in N, N-dimethylformamide (0.6 mL). Benzotriazol-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.050 g, 0.096 mmol) is added followed by N-methylmorpholine (0.015 mL, 0.137 mmol) and the mixture is reduced to .0. Stir for 25 hours. Benzylamine (0.011 mL, 0.101 mmol) was added and the mixture was stirred for 15.5 hours. The mixture was partitioned between ethyl acetate and lithium chloride (5% aqueous solution). The organic portion was washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil which was column chromatographed (ethyl acetate-hexanes 7: 3). Gave a colorless oil that was further purified by reverse phase preparative HPLC eluting with aqueous acetonitrile buffered with 0.1% trifluoroacetic acid. Fractions containing the required product were concentrated under reduced pressure to give methyl trifluoroacetate {6- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindole-1- Yl] -1-methyl-1H-benzimidazol-2-yl} carbamate was obtained as a colorless oil (0.014 g, 0.025 mmol, 19% yield). ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76-7.73 (m, 1H), 7.56-7.49 (m, 3H), 7.38-7.31 (m, 2H) 7.28-7.24 (m, 1H), 7.18-7.14 (m, 2H), 7.13-7.00 (m, 4H), 4.46 (d, 1H), 4 .29 (d, 1H), 3.74 (s, 3H), 3.56 (s, 3H); C 25 H 22 N 4 O 4 relates ^{MS (EI): 443 (MH} +).

Example 18: N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} Morpholine-4-carboxamide: 2-methyl-2-thiopseudourea hemisulphate (1.0 g, 3.6 mmol), 4-morpholinecarbonyl chloride (0.50 mL, 4.3 mmol), triethylamine (1.5 mL, 11 mmol) and The solution of N, N-dimethylformamide was stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate / 10% methanol and brine / saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted (2 × 100 mL ethyl acetate / 10% methanol). The organic layers were combined, dried (sodium sulfate), filtered, and concentrated in vacuo to give 0.78 g (> 100%) of crude methyl N- (morpholin-4-ylcarbonyl) imidothiocarbamate as a white solid. Was used in the next step without further purification. ¹ H NMR (400 MHz, d ₄ -MeOH): 4.89 (s, 3H), 3.65 (m, 4H), 3.27 (m, 4H); MS for C ₇ H ₁₃ N ₃ O ₂ S (EI): 204 (MH ^<+> ).

3- (3,4-Diaminophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one (0.10 g, 0.28 mmol) and methyl N- ( A solution of morpholin-4-ylcarbonyl) imidothiocarbamate (0.11 g, 0.56 mmol) in glacial acetic acid was heated at 85 ^° C. for 1.5 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted (2 × 100 mL ethyl acetate). The organic layers were combined, dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 1: 1 dichloromethane / acetone) was followed by preparative HPLC (reverse phase, acetonitrile / water with 0.1% trifluoroacetic acid). The pure fractions were neutralized with sodium bicarbonate, extracted with ethyl acetate, the organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration gave 0.0094 g (7%) of N- {6- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl]- 1H-benzimidazol-2-yl} morpholine-4-carboxamide was obtained. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.73 (dd, 1H), 7.55 (m, 2H), 7.33 (broad s, 1H), 7.27 (d, 1H), 7 .07-7.20 (m, 7H), 6.88 (t, 1H), 6.56 (s, 1H), 4.49 (d, 1H), 4.15 (d, 1H), 3. _{55 (m, 8H); C} 27 H 25 N 5 O 4 relates ^{MS (EI): 484 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
N-ethyl-N ′-{5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Urea: ¹ H NMR (400 MHz, d ₆ -DMSO): 11.46 (broad s, 1H), 9.86 (broad s, 1H), 7.73 (dd, 1H), 7.53 (m, 2H), 7.10-7.27 (m, 10H), 6.86 (broad s, 1H), 4.52 (d, 1H), 4.09 (d, 1H), 3.19 (m, _{2H), 1.10 (t, 3H} ); C 25 H 23 N 5 O 3 relates ^{MS (EI): 442 (MH} +).

N-ethyl-N ′-(5- {1-hydroxy-3-oxo-2-[(1R) -1-phenylmethyl] -2,3-dihydro-1H-isoindol-1-yl} -1H— Benzimidazol-2-yl} urea: ¹ H NMR (400 MHz, d ₆ -DMSO): 11.70 (m, 1H), 10.00 (m, 2H), 8.90 (m, 2H), 7. 78 (m, 2H), 7.66 (m, 1H), 7.60 (m, 2H), 7.52 (m, 3H), 7.39 (m, 2H), 7.19 (m, 14H) ), 7.02 (m, 4H), 6.56 (s, 2H), 4.35 (m, 2H), 4.55 (m, 1H), 4.40 (m, 1H), 3.19 (m, 8), 1.75 ( d, 2H), 1.44 (d, 2H), 1.29 (d, 4H), 1.10 (t, 14H); C 26 H ₅ N ₅ O ₃ relates ^{MS (EI): 456 (MH} +).

N ′-{5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -N, N-dimethylurea, trifluoroacetic acid (salt): ¹ H NMR (400 MHz, d ₆ -DMSO): 7.78 (d, 1H), 7.62 (broad s, 1H), 7.57 (m, 2H) ), 7.38 (d, 1H), 7.32 (s, 1H), 7.26 (d, 1H), 7.05-7.18 (m, 7H), 4.47 (d, 1H) , 4.20 (d, 1H), 3.02 (s, 6H); C 25 H 23 N 5 O 3 relates ^{MS (EI): 442 (MH} +).

N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -N′- (Phenylmethyl) urea, trifluoroacetic acid (salt): ¹ H NMR (400 MHz, d ₆ -DMSO): 8.02 (broad s, 1H), 7.77 (dd, 1H), 7.60 (s, 1H), 7.56 (dt, 2H), 7.36 (m, 5H), 7.27 (m, 3H), 7.14 (m, 5H), 7.02 (d, 1H), 4. 48 (d, 1H), 4.41 (d, 2H), 4.17 (d, 1H). _{C 30 H 25 N 5 O 3} S about ^{MS (EI): 504 (MH} +).

N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -N′- Methylurea, trifluoroacetic acid (salt): ¹ H NMR (400 MHz, d ₆ -DMSO): 7.78 (dd, 1H), 7.61 (broad s, 1H), 7.57 (m, 2H), 7.45 (d, 1H), 7.38 (d, 1H), 7.34 (broad s, 1H), 7.26 (dd, 1H), 7.06-7.19 (m, 6H), 4.48 (d, 1H), 4.15 (d, 1H), 2.76 (3H). MS about _{C 24 H 21 N 5 O 3} (EI): 428 (MH +).

N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} piperidine-1- Carboxamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.74 (d, 1H), 7.54 (m, 2H), 7.39 (broad s, 1H), 7.27 (d, 1H) 7.15 (m, 6H), 6.86 (d, 1H), 6.55 (broad s, 1H), 4.49 (d, 1H), 4.14 (d, 1H), 3.52 (S, 4H), 1.52 (m, 6H). MS about _{C 28 H 27 N 5 O 3} (EI): 483 (MH +).

N-ethyl-N ′-{6- [2- (4-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Il} urea: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.89 (d, 2H), 7.62-7.75 (m, 4H), 7.48 (m, 3H), 7. 14-7.34 (m, 4H), 3.25 (q, 2H), 1.13 (t, 3H); C 24 H 20 N 5 O 3 F relates ^{MS (EI): 446 (MH} +).

Example 19: 3- (4-Methylpiperazin-1-yl) propyl {6- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl ] -1H-benzimidazol-2-yl} carbamate: Sodium bicarbonate (6.73 g, 80.0 mmol) in a solution of 2-methyl-2-thiopseudourea sulfate (5.56 g, 20.0 mmol) in water (50 mL). ) And the reaction mixture was cooled to 0 ^° C. A solution of 3-chloropropyl chloroformate (2.41 mL, 20.0 mmol) in 1,4-dioxane (20 mL) was added dropwise and stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (250 mL) and the organic layer was separated. This was washed with water and brine, washed with anhydrous sodium sulfate and the solvent was evaporated. The resulting crude was purified by silica gel flash chromatography (eluent of hexane: ethyl acetate 7: 3 to 1: 1) to give 3-chloropropyl [imino (methylthio) methyl] carbamate (2.70 g, 64% yield). Was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.58 (br.s, 1H), 4.06 (t, 2H), 3.67 (t, 1H), 2.32 (s, 3H), _{2.02 (m, 2H); C} 6 H 11 ClN 2 O 2 S about ^{MS (EI): 211 (MH} +).

(3,4-Diaminophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one) (0.42 g, 1.21 mmol) and 3-chloropropyl [ A solution of imino (methylthio) methyl] carbamate (0.27 g, 1.31 mmol) in glacial acetic acid (5.0 mL) was heated at 80 ^° C. for 20 minutes. The reaction mixture was poured into ice water and the pH was adjusted to 9 by addition of 2M aqueous sodium hydroxide. The precipitated product was extracted with ethyl acetate (100 mL), the organic layer was washed with brine, dried over anhydrous sodium sulfate and then the solvent was evaporated. The resulting crude was purified by silica gel flash chromatography (eluent of chloroform-acetonitrile 95: 5 to 9: 1) to give 3-chloropropyl {6- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-Dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} acetate (0.64 g, 71% yield) was obtained. MS about _{C 26 H 23 ClN 4 O 4} (EI): 491 (MH +).

3-chloropropyl {6- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} acetate ( 0.25 g, 0.51 mmol) and 1-methyl - piperazine (0.46 mL, acetonitrile (5.0 mL) solution of 5.10 mmol), was heated at 80 ^o C. The reaction mixture was cooled to room temperature and the solvent was evaporated. The resulting crude was purified by reverse phase preparative HPLC (CH ₃ CN / 25 mM aqueous ammonium acetate). Fractions were collected and the solvent was concentrated. The aqueous residue was partitioned between ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine and dried over anhydrous sodium sulfate. Filtration and concentration gave a pale yellow residue which was lyophilized from a mixture of acetonitrile-water (1: 1, 3.0 mL) to give 3- (4-methylpiperazin-1-yl) propyl {6- [1-Hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} acetate (0.12 g, 43%) Got. ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.50 (br.s, 1H), 7.70 (d, 1H), 7.49 (m, 3H), 7.23 (t, 1H), 7.15 (m, 6H), 6.84 (d, 1H), 4.49 (d, 1H), 4.16 (t, 4H), 4.10 (d, 1H), 3.34 (s , 6H), 2.36 (m, 3H), 2.18 (s, 3H) ring-opened body, 2.16 (s, 3H) ring-closed body, 1.78 (m, 1H); C ₃₁ H ₃₄ N ₆ O ₄ on ^{MS (EI): 555 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
3-piperidin-1-ylpropyl {6- [2- (4-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.84 (m, 1H), 7.61 (m, 3H), 7.48 (m, 2H), 7.27 (m , 2H), 7.11 (m, 2H), 6.95 (m, 1H), 6.55 (m, 1H), 6.32 (m, 1H), 4.17 (m, 2H), 3 .98 (m, 1H), 2.34 (m, 4H), 1.81 (m, 1H), 1.49 (m, 6H); C 30 H 30 N 5 O 4 F relates MS (EI): 544 (MH ^<+> ).

3- (4-Methylpiperazin-1-yl) propyl {6- [2- (4-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.84 (d, 1H), 7.60 (m, 3H), 7.48 (m, 2H), 7.27 (d, 1H), 7.23 (d, 1H), 7.16 (m, 2H), 6.94 (d, 1H), 6.56 (s, 1H), 6.32 (s , 1H), 4.16 (t, 2H), 2.15-2.46 (m, 12H), 1.77 (m, 2H); C 30 H 31 N 6 O 4 F relates MS (EI): 559 (MH ^<+> ).

3-piperidin-1-ylpropyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H -Benzimidazol-2-yl} carbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ): 7.96 (s, 1H), 7.88 (d, 1H), 7.66 (m, 2H), 7.52 (m, 1H), 7. 39 (t, 1H), 7.35 (s, 1H), 7.28 (m, 2H), 7.21 (t, 1H), 7.07 (d, 1H), 4.07 (t, 2H) ), 3.42 (t, 2H), 3.26 (t, 4H), 1.90 (m, 2H), 1.48 (m, 2H), 1.37 (m, 4H); C ₃₀ H ₂₉ ClFN ₅ O ₄ on ^{MS (EI): 578 (MH} +).

Example 20: N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -4-piperidin-1-ylbutanamide: To a solution of ethyl 3-bromobutanoate (6.0 ml, 42 mmol) in N, N-dimethylformamide (20 ml) was added piperidine (8.0 ml, 80 mmol) at 0 ^° C. It was. The reaction mixture was warmed to 25 ^° C. and stirred for 16 hours, at which point it was diluted with ethyl acetate (200 ml). The organic layer was washed with 2.0N sodium hydroxide (4: 1 v / v) and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give ethyl 4-piperin-1-ylbutanoate (6.8 g) as brown Obtained as an oil. C ₁₁ H ₂₁ NO ₂ relates ^{MS (EI): 200 (MH} +).

To a solution of ethyl 4-piperin-1-ylbutanoate (6.8 g, 39 mmol) in ethanol (30 ml) was added potassium hydroxide (11 g, 0.20 mol) aqueous solution (40 ml) at 25 ⁰ C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and then dried under high vacuum for 2 days. The sodium salt of this acid was dissolved in chloroform (100 ml) as a slurry. To this slurry, a catalytic amount of N, N-dimethylformamide (0.2 ml) was added, then oxalyl chloride (15 ml, 170 mmol) was added dropwise at 25 ° C. and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain crude 4-piperin-1-ylbutanoyl chloride hydrochloride. To a suspension of 4-piperin-1-ylbutanoyl chloride chloride (about 40 mmol) and 2-methyl-2-thiopseudourea sulfate (5.6 g, 20 mmol) in acetonitrile (100 ml) was added triethylamine (20 ml) while cooling in an ice bath. 0.27 mol) was added dropwise. The reaction mixture was then warmed to 25 ^° C. over 1 hour. The reaction mixture was filtered through celite and the solid was washed with acetonitrile (100 ml). The filtrate was concentrated in vacuo to give crude 3-piperidin-1-ylpropyl [imino (methylthio) methyl] carbamate (10.6 g) as a brown oil. C ₁₁ H- ₂₁ N ₃ OS relates ^{MS (EI): 244 (MH} +).

3- (3,4-Diaminophenyl) -3-hydroxy-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-one (75 mg, 0.21 mmol) and 3-piperidine-1- A solution of ylpropyl [imino (methylthio) methyl] carbamate (200 mg, 0.5 mmol) in tert-butanol (15 ml) was heated to 85 ^° C. and stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting crude was purified by reverse phase HPLC to give N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindole. -1-yl] -1H-benzimidazol-2-yl} -4-piperidin-1-ylbutanamide, trifluoroacetate (40 mg, 36%) was obtained as a white solid. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.59 (brs, 1H), 7.54 (m, 2H), 7.36 (d, 1H), 7 .23 (d, 1H), 7.12-7.07 (m, 6H), 6.99 (d, 1H), 4.47 (d, 1H), 4.18 (d, 1H), 3. 40 (d, 2H), 3.03 (m, 2H), 2.83 (t, 2H), 2.56 (t, 2H), 1.97 (m, 2H), 1.81 (d, 2H) ), 1.68-1.58 (m, 3H) , 1.37 (m, 1H); C 31 H 33 N 5 O 3 relates ^{MS (EI): 524 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
3,3,3-trifluoro-2-hydroxy-N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl]- 1H-benzimidazol-2-yl} -2- (trifluoromethyl) propanamide): ¹ H NMR (400 MHz, d ₆ -DMSO): 7.75 (dd, 1H), 7.54-7.50 (m 3H), 7.24-7.22 (m, 2H), 7.13-7.10 (m, 5H), 6.95 (d, 1H), 4.44 (d, 1H), 4. _{20 (d, 1H); C} 26 H 18 F 6 N 4 O 4 relates ^{MS (EI): 565 (MH} +).

4,4,4-trifluoro-3-hydroxy-N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl]- 1H-benzimidazol-2-yl} -3- (trifluoromethyl) butanamide): ¹ H NMR (400 MHz, d ₆ -DMSO): 7.74 (dd, 1H), 7.56-7.49 (m , 3H), 7.30 (d, 1H), 7.23 (d, 1H), 7.16-7.09 (m, 5H), 6.95 (d, 1H), 4.46 (d, 1H), 4.16 (d, 1H ), 3.06 (s, 2H); C 27 H 20 F 6 N 4 O 4 relates ^{MS (EI): 579 (MH} +).

N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -3-piperidine -1-ylpropanamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.73 (dd, 1H), 7.56-7.49 (m, 3H), 7.28-7.24 (m, 2H) ), 7.19-7.10 (m, 5H), 6.85 (d, 1H), 4.50 (d, 1H), 4.09 (d, 1H), 5.58 (dd, 4H) , 2.37 (br m, 4H) , 1.86 (s, 2H), 1.49-1.46 (m, 4H), 1.36 (br m, 2H); C 30 H 31 N 5 O MS (EI) for ₃ : 510 (MH ^<+> ).

N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -4- [ (Phenylmethyl) oxy] butanamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.63 (br s, 1H), 7.59-7.51 (m, 3H ), 7.36 (d, 1H), 7.30-7.10 (m, 11H), 6.99 (d, 1H), 4.49 (d, 1H), 4.45 (s, 2H) , 4.15 (d, 1H), 3.50 (t, 2H), 2.58 (t, 2H), 1.92 (m, 2H); C 33 H 30 N 4 O 4 MS (EI) for : 547 (MH ^<+> ).

N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -4-piperidine -1-ylbutanamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.59 (br s, 1H), 7.54 (m, 2H), 7.36 (d , 1H), 7.23 (d, 1H), 7.12-7.07 (m, 6H), 6.99 (d, 1H), 4.47 (d, 1H), 4.18 (d, 1H), 3.40 (d, 2H), 3.03 (m, 2H), 2.83 (t, 2H), 2.56 (t, 2H), 1.97 (m, 2H), 1. 81 (d, 2H), 1.68-1.58 (m, 3H), 1.37 (m, 1H); C ₃₁ H ₃₃ N ₅ O ₃ MS (EI): 524 (MH ^<+> ).

N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -4- ( 4-Methylpiperazin-1-yl) butanamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.76 (d, 1H), 7.59 (br s, 1H), 7.55 (m, 3H) 7.37 (d, 1H), 7.23 (d, 1H), 7.14-7.07 (m, 5H), 6.99 (d, 1H), 4.48 (d, 1H), 4.16 (d, 1H), 3.02 (t, 3H), 2.81 (s, 3H), 2.56 (t, 2H), 1.94 (m, 2H); C 31 H 34 N ₆ O related to _{MS (EI) 3: 539 (} MH +).

N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -4-pyrrolidine -1-ylbutanamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 11.83 (br s, 1 H), 9.53 (br s, 1 H), 7.75 (d, 1 H), 7.57 ( br s, 1H), 7.54 (m, 2H), 7.32 (d, 1H), 7.26 (d, 1H), 7.22-7.11 (m, 5H), 6.92 ( d, 1H), 4.50 (d, 1H), 4.11 (d, 1H), 3.17 (m, 2H), 3.01 (brs, 2H), 2.55 (t, 2H) , 2.05-1.93 (m, 4H), 1.90-1.81 (m, 4H); C 30 H 31 N 5 O Seki That _{MS (EI) 3: 510 (} MH +).

4- (Diethylamino) -N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- Il} butanamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 9.21 (br s, 1 H), 7.76 (d, 1 H), 7.59 (br s, 1 H), 7.55 (m , 2H), 7.35 (d, 1H), 7.22-7.11 (m, 5H), 6.96 (d, 1H), 4.51 (d, 1H), 4.11 (d, 1H), 3.19-1.91 (m, 2H ), 2.60 (t, 2H), 1.98-1.91 (m, 2H), 1.21 (t, 6H); C 30 H ₃₃ N ₅ O ₃ relates ^{MS (EI): 512 (MH} +).

N- {5- [2- (4-Fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -4 -Piperidin- ¹ -ylbutanamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.84 (d, 1H), 7.63-7.55 (m, 3H), 7.42-7.30 (m , 3H), 7.24 (d, 2H), 7.11-7.04 (m, 2H), 3.39 (d, 2H), 3.01 (t, 2H), 2.81 (t, 2H), 2.54 (t, 2H), 1.94 (m, 2H), 1.80 (d, 2H), 1.68-1.54 (m, 3H), 1.37 (m, 1H) _{); C 30 H 30 FN 5} O 3 relates ^{MS (EI): 527 (MH} +).

N- {5- [2- (3-Chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} -4-piperidin-1-ylbutanamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 12.02 (brs, 1H), 11.52 (brs, 1H), 7.87 (d, 1H) ), 7.72 (s, 1H), 7.67-7.57 (m, 2H), 7.48 (t, 1H), 7.40-7.23 (m, 3H), 7.16 ( t, 1H), 6.90 (d, 1H), 3.35 (t, 6H), 2.41 (t, 1H), 2.31-2.24 (m, 4H), 1.74 (m , 2H), 1.45 (m, 3H), 1.32 (m, 1H); about C 30 H 29 _CFN 5 _{O 3} ^{S (EI): 562 (MH} +).

N- {6- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -2-methyl Propanamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 12.01 (s, 1H), 11.46 (d, 1H), 7.71 (d, 1H), 7.64-7.40 (M, 3H), 7.34-7.10 (m, 8H), 6.83 (m, 1H), 4.50 (d, 2H), 2.72 (m, 1H), 1.13 ( _{d, 6H); C 26 H} 24 N 4 O 3 relates ^{MS (EI): 441 (MH} +).

N- {6- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} pent-4- Inamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.79 (m, 2H), 7.53-7.46 (m, 2H), 7.34 (d, 1H), 7.26-7 .17 (m, 2H), 7.10 (m, 2H), 7.05 (m, 3H), 4.52 (d, 1H), 4.24 (d, 1H), 2.91 (t, 2H), 2.64 (tt, 2H ), 2.01 (t, 1H); C 27 H 22 N 4 O 3 relates ^{MS (EI): 451 (MH} +).

2,2-difluoro-N- {6- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- yl} _{cyclopropanecarboxamide: C 26 H 20 N 4 O} 3 F 3 relates ^{MS (EI): 475 (MH} +).

N- {6- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -2,2 -Dimethyl-3-piperidin-1-ylpropanamide: ¹ H NMR (400 MHz, d ₆ -CDCl ₃ ): 7.81 (m, 1H), 7.46 (m, 3H), 7.16-7.26 ( m, 4H), 7.15-7.25 (m, 2H), 7.03 (d, 2H), 4.76 (d, 1H), 4.54 (dd, 2H), 3.53 (d , 4H), 2.05 (s, 3H), 1.64 (d, 3H), 1.39 (d, 3H), 1.28 (s, 1H), 1.23 (d, 2H), 1 _{.21 (s, 1H); C} 32 H 35 N 5 O 3 relates ^{MS (EI): 538 (MH} +).

Trifluoroacetic acid N- {5- [1-hydroxy-3-oxo-2- (phenylmethyl) -2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} propanamide : ¹ H NMR (400 MHz, d ₆ -DMSO): 12.0-11.9 (s, 1H), 11.5-11.4 (s, 1H), 7.74-7.69 (d, 1H) ), 7.57-7.45 (m, 2H), 7.31-7.05 (m, 7H), 6.83-6.78 (d, 1H), 4.55-4.45 (s) , 1H), 4.14-4.04 (d, 1H), 2.84-2.76 (m, 1H), 2.46-2.38 (m, 1H), 1.32-1.26. (m, 1.5H), 1.12-1.06 ( m, 1.5H); C 25 H 22 N 4 O 3 MS (EI) for 427 ^(MH +).

Example 21: Methyl (6- {1-methyl-3-oxo-2- [3- (trifluoromethyl) phenyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole 2-yl) carbamate: To a mixture of methyltriphenylphosphonium bromide (15.6 g, 44 mmol) in tetrahydrofuran (100 mL) at 0 ^° C. sodium hexamethyldisilazide (22 mL, 2.0 M solution in THF, 44 mmol) was added and the resulting mixture was stirred at 0 ^° C. for 1 h. Then methyl 2-[(4-chloro-3-nitrophenyl) carbonyl] benzoate (7.0 g, 22 mmol) in tetrahydrofuran (50 mL) was added dropwise to the yellow reaction mixture and 30 minutes at 0 ^° C. at room temperature. For 4 hours. The brown reaction mixture is diluted with hexanes and filtered through silica gel and the filtrate is washed with water (100 mL), brine solution (100 mL), dried over sodium sulfate, filtered, concentrated and flash chromatographed (silica gel, Purification by elution with 5-10% ethyl acetate-hexane) gave methyl 2- [1- (4-chloro-3-nitrophenyl) ethenyl] benzoate (0.95 g, 3 mmol, 14% yield). ¹ H NMR (400 MHz, CDCl ₃ ): 7.95-7.93 (dd, 1H), 7.73-7.72 (d, 1H), 7.61-7.57 (dt, 1H), 7 .50-7.46 (dt, 1H), 7.46-7.43 (d, 1H), 7.39-7.34 (m, 2H), 5.77 (s, 1H), 5.37 _{(s, 1H), 3.63 (} s, 3H); C 16 H 12 ClNO 4 relates ^{MS (EI): 318 (MH} +).

Methyl 2- [1- (4-chloro-3-nitrophenyl) ethenyl] benzoate (0.95 g, 3.0 mmol) was suspended in methanol (45 mL) and 2N sodium hydroxide (100 mL) at 65 ^° C. Stir for 2 hours. The reaction mixture was concentrated to acidify to pH 4 and then extracted with ethyl acetate (3 × 50 mL). The combined extracts were washed with water (100 mL), brine solution (100 mL), dried over sodium sulfate, filtered and concentrated to 2- [1- (4-chloro-3-nitrophenyl) ethenyl] benzoic acid ( 0.81 g, 2.7 mmol, 90% yield). ¹ H NMR (400 MHz, CDCl ₃ ): 7.92-7.91 (d, 1H), 7.85-7.83 (dd 1H), 7.70-7.67 (d, 1H), 7. 66-7.62 (dt, 1H), 7.54-7.50 (dt, 1H), 7.38-7.35 (m, 2H), 5.93 (s, 1H), 5.37 ( s, 1 H); MS (EI) for C ₁₅ H ₁₀ ClNO ₄ : 302 (M ⁻ ).

Benzotriazol-1-yl-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate (1.21 g, 2.6 mmol) was dissolved in 2- [1- (4-chloro-3-nitrophenyl) ethenyl in DMF (2 mL). ] To a mixture of benzoic acid (0.78 g, 2.6 mmol) and diisopropylethylamine (1.12 mL, 6.4 mmol) and stirred for 10 minutes, 3-aminobenzotrifluoroid (0.38 mL, 3.1 mol) was added. added. The resulting mixture was stirred at room temperature for 18 hours, diluted with ethyl acetate (50 mL), washed with 30 mL each of 20% aqueous citric acid, saturated sodium bicarbonate solution, then brine solution, dried over sodium sulfate, filtered And concentrated. The residue was purified by flash chromatography (silica gel, eluted with 5-15% ethyl acetate-hexane) to give 2- [1- (4-chloro-3-nitrophenyl) ethenyl] -N- [3- (trifluoromethyl) phenyl. Benzamide (0.82 g, 1.8 mmol, 69% yield) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ): 7.69-7.35 (m, 11H), 5.82 (s, 1H), 5.62 (s, 1H); C ₂₂ H ₁₄ ClF ₃ N ₂ O MS (EI) for ₃ : 447 (MH ^<+> ).

2- [1- (4-Chloro-3-nitrophenyl) ethenyl] -N- [3- (trifluoromethyl) phenyl] benzamide (0.72 g, 1.6 mmol), sodium azide (3.1 g, 4 .8 mmol) and N, N-dimethylformamide (2 mL) were stirred at 60 ^° C. for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (3 × 30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated to an oily residue. This residue was dissolved in tetrahydrofuran, cooled to 0 ^° C., sodium borohydride (0.11 g, 2.7 mmol) was added, and stirring was continued at room temperature for 30 minutes. The reaction mixture was quenched with methanol (2 mL), concentrated and then diluted with ethyl acetate (50 mL). The organic solution was washed with water (30 mL) and then brine solution (30 mL), then dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, eluted with 15-50% ethyl acetate-hexane) to give 2- [1- (4-amino-3-nitrophenyl) ethenyl] -N- [3- (trifluoromethyl) phenyl. Benzamide (0.35 g, 0.8 mmol, 50% yield) was obtained. MS about _{C 22 H 16 F 3 N 3} O 3 (EI): 428 (MH +).

2- [1- (4-Amino-3-nitrophenyl) ethenyl] -N- [3- (trifluoromethyl) phenyl] benzamide (0.35 g, 0.80 mmol) and iron powder (5 mL) in acetic acid (5 mL) 0.91 g, 164 mmol) was stirred vigorously at 50 ^° C. for 2 hours. The reaction mixture was concentrated. Ice (about 30 g) and 50% sodium hydroxide solution were added until the pH remained basic. The mixture is extracted with ethyl acetate (3 × 20 mL) and the combined extracts are washed with water (30 mL) then brine (30 mL), then dried over sodium sulfate, filtered and concentrated to an oily residue. Got. The residue was dissolved in acetic acid (5 mL) containing 1,3-bis (methoxycarbonyl) -2-methyl-2-thiopseurea (0.17 g, 0.80 mmol) and stirred at 70 ^° C. for 20 minutes. . The reaction mixture was concentrated. Ice (ca. 20 g) and solid sodium bicarbonate were added until the pH remained basic. The mixture is extracted with ethyl acetate (3 × 20 mL) and the combined extracts are washed with water (30 mL) then brine (30 mL), then dried over sodium sulfate, filtered and concentrated to an oily residue. Got. The crude is dissolved in ethyl acetate (30 mL), 10% palladium-carbon (200 mg) is added, and the resulting mixture is hydrogenated at 45 psi for 18 hours in a Parr apparatus until consumption of olefin-like impurities that interfere with subsequent purification steps. Turned into. The mixture was filtered and concentrated, and the crude was purified by reverse phase preparative HPLC (acetonitrile-0.1% trifluoroacetic acid in water eluent). Fractions containing pure product were concentrated then basified with sodium bicarbonate and extracted with ethyl acetate (150 mL). Concentration of the extract gave 82 mg of white solid, which was dissolved in acetonitrile (2 mL). To this solution was added hydrogen chloride in dioxane (43 μL, 4M, 1.6 mmol) and water (15 mL). This solution was lyophilized to methyl hydrochloride (6- {1-methyl-3-oxo-2- [3- (trifluoromethyl) phenyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazol-2-yl) carbamate (88 mg, 0.17 mmol, 21% yield) was obtained. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.91-7.89 (d, 1H), 7.67-7.49 (m, 7H), 7.39-7.37 (d, 1H) , 7.25-7.21 (m, 2H), 3.83 (s, 3H), 2.02 (s, 3H); C 25 H 19 F 3 N 4 O 3 relates MS (EI): 481 ( MH ^<+> ).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
Methyl hydrochloride {6- [2- (3-bromophenyl) -1-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.89, 7.87 (d, 1H), 7.65-7.61 (dd, 1H), 7.57-7.54 (dd, 1H) 7.50-7.43 (m, 4H), 7.35-7.33 (d, 1H), 7.26-7.22 (dd, 1H), 7.14-7.10 (m, 1H), 6.93-6.91 (d, 1H ), 3.81 (s, 3H), 1.99 (s, 3H); C 24 H 19 BrN 4 O 3 relates MS (EI): 491 ( MH ^<+> ).

Example 22 N- {6- [2- (3-Chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benz Imidazole-2-yl} -2,2-difluorocyclopropanecarboxamide: To a solution of 2- (4-chloro-3-nitrobenzoyl) benzoic acid (6.76 g, 22.00 mmol) in anhydrous dichloromethane (35 ml), 0 ^o Pyridine (1.80 ml, 22.00 mmol) was added at C followed by dropwise addition of cyanuric fluoride (2.0 ml, 24.20 mmol) in dichloromethane (4.0 mL). The reaction mixture was stirred at 0 ^° C. for 100 minutes. Water (35 mL) was added to the reaction mixture and stirred at 0 ^° C. for 10 minutes. The resulting slurry was filtered through a celite pad and washed with dichloromethane. The filtrate was partitioned between water and dichloromethane, and the dichloromethane layer was washed with water and dried over anhydrous sodium sulfate. Filtration and concentration gave 3- (4-chloro-3-nitrophenyl) -3-fluoro-2-benzofuran-1 (3H) -one (6.10 g, 90% yield) as a crystalline solid. Was used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.34 (d, J = 2 Hz, 1H), 8.20 (dd, J ₁ = 8 Hz, J ₂ = 0.8 Hz, 1H), 8.01− 7.94 (m, 3H), 7.86 (td, J ₁ = 8 Hz, J ₂ = 1.2 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H); C ₁₄ H ₇ ClFlNO ₄ about the ^{MS (EI): 306 (M} -).

To a solution of 3- (4-chloro-3-nitrophenyl) -3-fluoro-2-benzofuran-1 (3H) -one (6.10 g, 20.00 mmol) in 1,2-dichloroethane (40 mL) was added 2- Fluoro-3-chloroaniline (3.50 g, 24.00 mmol) was added followed by N, N-dimethylaniline (3.90 mL, 32.00 mmol). The reaction mixture was stirred at 70 ^° C. for 20 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (150 mL). This was washed with 20% citric acid (2 × 30 mL), water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave a semi-solid product that was triturated with hexane (60 mL). The crystalline product is collected by filtration; it is dried under reduced pressure to give 2- (3-chloro-2-fluorophenyl) -3- (4-chloro-3-nitrophenyl) -3-hydroxy-2, 3-Dihydro-1H-isoindol-1-one (7.23 g, 84% yield) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): 7.95 (d, J = 1.2 Hz, 1H), 7.94 (s, 1H), 7.76-7.66 (m, 2H), 7. 56 (d, J = 8.8 Hz, 1H), 7.49-7.46 (m, 2H), 7.42 (d, J = 1.2 Hz, 1H), 7.32 (td, J ₁ = _{6.8Hz, J 2 = 1.6Hz, 1H} ), 7.16 (td, J 1 = 8Hz, J 2 = 1.2Hz, 1H); C 20 H 11 Cl 2 FN 2 O 4 MS (EI) for : 433 ^(M -).

2- (3-Chloro-2-fluorophenyl) -3- (4-chloro-3-nitrophenyl) -3-hydroxy-2,3-dihydro-1H-isoindol-1-one (7.22 g, 17 .00 mmol) in N, N-dimethylformamide (20 ml) was added sodium azide (1.80 g, 28.00 mmol) and the reaction mixture was stirred at 40 ^° C. for 20 hours. This was cooled to room temperature and poured into ice water. A pale yellow product precipitated and was collected by filtration. When this was washed with water and dried under reduced pressure, 3- (4-azido-3-nitrophenyl) -2- (3-chloro-2-fluorophenyl) -3-hydroxy-2,3-dihydro-1H-isoindole-1 -On (7.0 g, 95% yield) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): 7.97-7.93 (m, 2H), 7.74-7.65 (m, 2H), 7.51 (dd, J ₁ = 8.4 Hz, _{J 2 = 2Hz, 1H),} 7.45-7.39 (m, 2H), 7.34 (td, J 1 = 8Hz, J 2 = 1.2Hz, 1H), 7.15 (td, J 1 = 8.4 Hz, J ₂ = 1.6 Hz); MS (EI) for C ₂₀ H ₁₁ ClFN ₅ O ₄ : 438 (M ⁻ ).

3- (4-azido-3-nitrophenyl) -2- (3-chloro-2-fluorophenyl) -3-hydroxy-2,3- in a tetrahydrofuran-water mixture (1: 1, 15.0 ml). To a solution of dihydro-1H-isoindol-1-one (7.0 g, 16.00 mmol) was added ammonium formate (5.0 g, 79.30 mmol), followed by iron (4.0 g, 71.60 mmol). It was. The reaction mixture was heated to reflux and stirred for 320 minutes. This was cooled to room temperature and diluted with ethyl acetate (70 mL). The resulting slurry was filtered through a celite pad and washed with ethyl acetate (3 × 30 mL). This was partitioned into water and the organic layer was washed with water (30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. Filtration and concentration yielded a yellow oily product. This was crystallized from diethyl ether by the addition of hexane. The product was collected by filtration and dried under reduced pressure to give 2- (3-chloro-2-fluorophenyl) -3- (3,4-diaminophenyl) -3-hydroxy-2,3-dihydro-1H-isoindole- 1-one (3.42 g, 56% yield) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): 7.85 (d, J = 7.6 Hz, 1H), 7.65-7.58 (m, 2H), 7.41-7.34 (m, 2H) ), 7.17 (t, J = 6.4 Hz. 1H), 7.05 (t, J = 8 Hz, 1H), 6.69 (s, 1H), 6.57 (s, 2H); C ₂₀ H ₁₅ ClFN ₃ O ₂ relates ^{MS (EI): 382 (M} -).

To a solution of 2,2-difluorocyclopropanecarboxylic acid (0.5 g, 4.10 mmol) in dichloromethane (25 mL) was added pyridine (0.36 mL, 4.51 mmol) and the reaction mixture was cooled to 0 ^° C. A solution of cyanuric fluoride (0.34 mL, 4.10 mmol) in dichloromethane (5.0 mL) was added dropwise and the mixture was stirred for 2 hours. Water (5.0 mL) was added and stirring was continued for an additional 10 minutes. This was diluted with dichloromethane (100 mL) and the slurry was filtered through a celite pad. Wash the filtrate with water and brine, dry over anhydrous sodium sulfate and evaporate the solvent to give 2,2-difluorocyclopropanecarbonyl fluoride (0.50 g, quantitative), which is further purified Used without. A suspension of 2-methyl-2-thiopseudourea sulfate (0.28 g, 2.65 mmol) in dichloromethane (5.0 mL) and pyridine (0.21 mL, 2.65 mmol) was fluorinated at 0 ^° C. , 2-Difluorocyclopropanecarbonyl in dichloromethane (3.0 mL) was added and the reaction mixture was stirred at room temperature for 15 hours. Ethyl acetate (100 mL) was added to the mixture, which was washed with 1M hydrochloric acid and brine. The solvent was washed with anhydrous sodium sulfate and evaporated. The crude product was purified by silica gel flash chromatography (hexane: ethyl acetate 7: 3 to 1: 1 eluent) to give methyl N, N′-bis [(2,2-difluorocyclopropyl) carbonyl] imidothiocarbamate (0. 72 g, 59% yield). _{C 10 H 10 F 4 N 2} O 2 S about ^{MS (EI): 299 (MH} +).

2- (3-Chloro-2-fluorophenyl) -3- (3,4-diaminophenyl) -3-hydroxy-2,3-dihydro-1H-isoindol-1-one (0.25 g, 0.65 mmol) ) And methyl N, N′-bis [(2,2-difluorocyclopropyl) carbonyl] imidothiocarbamate (0.21 g, 0.72 mmol) in n-butanol (2.0 mL) at 80 ^° C. with 5 Heated for hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The resulting crude was purified by reverse phase preparative HPLC (acetonitrile / 25 mM aqueous ammonium acetate eluent). Fractions were collected and the solvent was concentrated. The residue was partitioned in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Filtration and concentration gave a pale yellow oily residue which was lyophilized from a mixture of acetonitrile-water (5.0 mL) to give N- {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy. -3-Oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} -2,2-difluorocyclopropanecarboxamide (48 mg, 38% yield) was obtained. . ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.18 (s, 1H), 7.88 (m, 1H), 7.75 (s, 1H), 7.63 (m, 2H), 7. 48 (m, 1H), 7.30 (m, 3H), 7.16 (m, 1H), 6.93 (m, 1H), 2.92 (m, 1H), 2.09 (m, 2H) _{); C 25 H 16 ClF 3} N 4 O 3 relates ^{MS (EI): 513 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
N- (5- {1-hydroxy-3-oxo-2- [3- (phenyloxy) phenyl] -2,3-dihydro-1H-isoindol-1-yl} -1H-benzimidazole-2-hydrochloride Yl) -4-piperidin-1-ylbutanamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.03 (s, 1 H), 7.84 (d, 1 H), 7.78 (br s, 1 H) 7.64-7.55 (m, 3H), 7.41 (d, 1H), 7.32-7.25 (m, 4H), 7.20 (s, 1H), 7.11-7 .07 (m, 2H), 6.81-6.75 (m, 3H), 3.44-3.35 (m, 4H), 3.08-3.01 (m, 2H), 2.92 -2.79 (m, 2H), 2.66-2.60 (m, 2H), 2.11-2.19 (m, 2H), _{3-1.65 (m, 4H); C} 36 H 35 N 5 O 5 relating ^{MS (EI): 602 (MH} +).

Cyclobutyl hydrochloride {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.96-7.94 (b, 1H), 7.91-7.89 (d, 1H), 7.71-7.60 ( m, 3H), 7.54-7.50 (t, 1H), 7.44-7.42 (d, 1H), 7.39-7.35 (t, 1H), 7.32-7. 30 (d, 1H), 7.22-7.13 (m, 2H), 5.08-5.01 (m, 1H), 2.40-2.30 (m, 2H), 2.18- 2.08 (m, 2H), 1.85-1.76 (m, 1H), 1.70-1.61 (m, 1H); C 26 MS regarding _{H 20 ClFN 4 O 4 (EI} ): 517 (MH +).

2,2-difluoroethyl hydrochloride {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H- Benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.94-7.92 (b, 1H), 7.88-7.87 (d, 1H), 7.67 -7.60 (m, 2H), 7.58-7.56 (b, 1H), 7.50-7.44 (dd, 1H), 7.41-7.39 (d, 1H), 7 .37-7.33 (d, 1H), 7.30-7.28 (d, 1H), 7.19-7.15 (dd, 1H), 7.12-7.10 (d, 1H) , 6.48-6.19 (tt, 1H), 4.55-4.47 (dt, 2H); C 24 H 16 Cl ₃ N ₄ O ₄ relates ^{MS (EI): 517 (MH} +).

But-2-yn-1-yl {5- [2- (4-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole -2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 11.70 (roads, 1H), 7.84 (dd, 1H), 7.58 (m, 3H), 7.47 (M, 2H), 7.28 (d, 1H), 7.24 (d, 1H), 7.13 (m, 2H), 6.95 (dd, 1H), 4.77 (m, 2H) _{, 1.85 (3H); C 26} H 19 N 4 O 4 F relates ^{MS (EI): 471 (MH} +).

(1-Methylpiperidin-2-yl) methyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl ] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.66 (7.64 (m, 2H), 7.49 (T, 1H), 7.43 (broads, 1H), 7.33 (m, 2H), 7.23 (d, 1H), 7.17 (t, 1H), 6.92 (d, 1H) ), 4.19 (m, 2H), 2.76 (d, 1H), 2.23 (s, 3H), 2.06 (m, 2H), 1.70 (m, 2H), 1.20 _{-1.51 (m, 4H); C} 29 H 27 N 5 O 4 ClF relates MS (EI): 564 MH ^+).

[(2S) -1-methylpyrrolidin-2-yl] methyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindole -1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.64 (m, 2H), 7.49 (T, 1H), 7.45 (broads, 1H), 7.31 (m, 2H), 7.24 (d, 1H), 7.17 (t, 1H), 6.91 (d, 1H) ), 4.09 (d, 2H), 2.93 (m, 1H), 2.45 (m, 1H), 2.32 (s, 3H), 2.16 (q, 1H), 1.56 _{-1.67 (m, 4H); C} 28 H 25 N 5 O 4 ClF relates MS (EI): 550 MH ^+).

Octahydro-2H-quinolinidin-1-ylmethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.73 (broads, 1H), 7.64 (m, 2H) 7.49 (t, 1H), 7.43 (roads, 1H), 7.32 (m, 2H), 7.23 (d, 1H), 7.17 (t, 1H), 6.91 (d, 1H), 4.32 ( m, 2H), 2.73 (d, 2H), 1.19-1.91 (m, 13H); C 32 H 31 N 5 O 4 ClF relates MS (EI ): 604 (MH ⁺ ).

1-methylethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.73 (s, 1H), 7.65 (m, 2H), 7.49 (m , 2H), 7.31 (m, 2H), 7.24 (d, 1H), 7.18 (dt, 1H), 6.91 (dd, 1H), 6.57 (s, open), 4 .95 (m, 1H), 1.27 (d, 6H); C 25 H 20 N 4 O 4 ClF relates ^{MS (EI): 495 (MH} +).

Cyclopropylmethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Il} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.86 (d, 1H), 7.73 (s, 1H), 7.63 (m, 2H), 7.39 (m, 2H), 7.31 (m, 2H), 7.24 (d, 1H), 7.17 (t, 1H), 6.91 (d, 1H), 6.56 (s, open), 3. 99 (d, 2H), 1.15 (m, 1H), 0.54 (m, 2H), 0.32 (m, 2H); C 26 H 20 N 4 O 4 ClF relates MS (EI): 507 (MH ⁺ ).

Tetrahydrofuran-2-ylmethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole -2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.73 (s, 1H), 7.63 (m, 2H), 7.48 ( m, 2H), 7.33 (m, 2H), 7.24 (d, 1H), 7.17 (dt, 1H), 6.91 (d, 1H), 6.56 (s, open), 4.10 (m, 2H), 3.76 (m, 1H), 3.65 (m, 1H), 1.79-1.99 (m, 3H), 1.61 (m, 1H); C ₂₇ H ₂₂ N ₄ O ₅ ClF relates ^{MS (EI): 537 (MH} +).

(1-Methylpiperidin-4-yl) methyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl ] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.88 (d, 1H), 7.68 (dd, 1H), 7.63 (dd, 1H) ), 7.55 (s, 1H), 7.48 (dd, 1H), 7.39 (d, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.17 (Dd, 1H), 7.09 (d, 1H), 4.09 (d, 2H), 3.41 (d, 2H), 2.91 (t, 2H), 2.74 (s, 3H) _{, 1.40 (q, 2H);} C 29 H 27 ClFN 5 O 4 relates MS (EI): 564 MH ^+).

2- (1-Methylpiperidin-4-yl) ethyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindole-1 -Yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.88 (d, 1H), 7.84 (s, 1H), 7.67 (dd , 1H), 7.62 (dd, 1H), 7.55 (s, 1H), 7.50 (dd, 1H), 7.37-7.30 (m, 3H), 7.17 (dd, 1H), 7.03 (d, 1H), 4.35 (t, 2H), 3.41 (d, 2H), 2.87 (t, 1H), 1.89 (d, 2H), 1. 64 (m, 4H), 1.37 (m, 2H); C 30 H 29 ClFN 5 O 4 relates MS (E ): 577 ^(MH +).

2,2,3,3-tetrafluorocyclobutyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindole-1- Yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, CDCl ₃ ): 7.85 (d, 1H), 7.72 (s, 1H), 7.55-749 (m, 2H), 7.37 (d, 1H), 7.24-7.18 (m, 3H), 7.08 (dd, 1H), 6.89 (dd, 1H), 5.20 (m, 1H) ), 2.98 (m, 1H) , 2.79 (m, 1H); C 26 H 16 ClF 5 N 4 O 4 relates ^{MS (EI): 579 (MH} +).

1-acetyl-N- {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benz Imidazol-2-yl} piperidine-4-carboxamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.89 (d, 1H), 7.86 (s, 1H), 7.67 (dd, 1H) 7.63 (dd, 1H), 7.57 (s, 1H), 7.50 (dd, 1H), 7.38 (d, 1H), 7.33 (dd, 1H), 7.30 ( d, 1H), 7.17 (dd, 1H), 7.05 (d, 1H), 3.08 (m, 1H), 2.75 (m, 1H), 2.62 (m, 1H), 1.87 (t, 2H), 1.59 (q, 2H), 1.44 (q, 2H); C 29 H 25 Cl MS on the _{N 5 O 4 (EI):} 562 (MH +).

N- {5- [2- (3-Chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} cyclobutanecarboxamide: ¹ H NMR (400 MHz, CDCl ₃ ): 8.23 (s, 1H), 7.96 (d, 1H), 7.63-7.52 (m, 4H), 7.34 ( d, 1H), 7.13 (d, 1H), 7.08 (dd, 1H), 6.95 (m, 1H), 6.89 (m, 1H), 3.35 (m, 1H), 2.37 (m, 2H), 1.97 (m, 2H), 0.86 (m, 2H); C 26 H 20 ClFN 4 O 3 relates ^{MS (EI): 491 (MH} +).

N- {5- [2- (3-Chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- Il} cyclopropanecarboxamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 12.34 (s, 1H), 7.89 (d, 1H), 7.84 (s, 1H), 7.67 (dd , 1H), 7.62 (dd, 1H), 7.56 (s, 1H), 7.50 (dd, 1H), 7.38-7.30 (m, 3H), 7.18 (dd, 1H), 7.03 (d, 1H ), 1.96 (m, 1H), 0.95 (m, 4H); C 25 H 18 ClFN 4 O 4 relates ^{MS (EI): 477 (MH} +).

2- (Methyloxy) ethyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H- Benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.67 (dd, 1H), 7.62 (dd, 1H), 7. 57 (s, 1H), 7.46 (dd, 1H), 7.40 (d, 1H), 7.31 (dd, 1H), 7.27 (d, 1H), 7.15 (dd, 1H) ), 7.09 (d, 1H) , 4.31 (m, 2H), 3.57 (m, 2H), 3.24 (s, 3H); C 25 H 20 ClFN 4 O 5 relating MS (EI ): 511 (MH ⁺ ).

N- {5- [2- (3-Chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} -2- (2-thienyl) acetamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.86 (d, 1H), 7.66 (dd, 1H), 7.62 (dd, 1H) 7.62 (dd, 1H), 7.55 (s, 1H), 7.46 (dd, 1H), 7.38 (m, 1H), 7.32-7.26 (m, 2H), 7.14 (dd, 1H), 7.04 6.96 (m, 3H), 4.02 (s, 2H); C 27 H 18 ClFN 4 O 3 S about ^{MS (EI): 533 (MH} +) .

N- {5- [2- (3-Chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2- IL} -N, N-diethylpentanediamide: ¹ H NMR (400 MHz, CDCl ₃ ): 7.97 (d, 1H), 7.84 (s, 1H), 7.67 (m, 4H), 7. 46 (d, 1H), 7.30 (m, 1H), 6.79 (dd, 1H), 6.91 (dd, 1H), 3.34 (m, 4H), 2.71 (t, 2H) ), 2.08 (m, 2H) , 1.21 (t, 3H), 1.09 (t, 3H); C 30 H 29 ClFN 5 O 4 relates ^{MS (EI): 578 (MH} +).

N- {6- [2- (4-Fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} butanamide: _{C 25 H 21 N 4 O 3} F relates ^{MS (EI): 445 (MH} +).

N- {6- [2- (4-Fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} propanamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 11.53 (roads, 1H), 7.84 (d, 1H), 7.63-7.55 (m, 3H), 7.48 (m, 2H), 7.28 (d, 2H ), 7.10 (t, 2H), 6.96 (d, 1H), 2.43 (q, 2H), 1.09 (t, 3H); C 24 H ₁₉ N ₄ O ₃ F relates ^{MS (EI): 431 (MH} +).

N- {6- [2- (4-Fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} peny- 4-Inamide: ¹ H NMR (400 MHz, d ₆ -DMSO): 12.04 (broad s, 1H), 11.60 (s, 1H), 7.85 (d, 1H), 7.45-7. 63 (m, 5H), 7.28 (d, 2H) 7.11 (t, 2H), 6.95 (d, 1H), 2.82 (s, 1H), 2.63 (t, 2H) _{; C 26 H 19 N 4 O} 3 F relates ^{MS (EI): 455 (MH} +).

(1-Methylpiperidin-3-yl) methyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl ] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.74 (s, 1H), 7.64 (m, 2H) ), 7.4 (m, 2H), 7.32 (q, 2H), 7.24 (d, 1H), 7.17 (t, 1H), 6.92 (d, 1H), 4.06 (Q, 1H), 3.99 (q, 1H), 2.73 (d, 1H), 2.62 (d, 1H), 2.50 (m, 3H), 2.15 (s, 4H) , 1.91 (s, 1H), 1.76 (m, 2H), 1.46 (m, 1H), 0.99 (m, 1H); C 2 H ₂₇ N ₅ O ₄ FCl relates ^{MS (EI): 565 (MH} +).

8-Azabicyclo [3.2.1] oct-3-ylmethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindole -1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.64 (m, 2H), 7.46 (M, 2H), 7.32 (m, 2H), 7.24 (d, 1H), 7.16 (t, 1H), 6.92 (d, 1H), 4.16 (d, 2H) 3.47 (s, 2H), 2.05 (m, 1H), 1.92 (m, 2H), 1.83 (s, 3H), 1.77 (m, 1H), 1.67 ( _{d, 1H), 1.42 (d} , 1H); C 30 H 27 N 5 O 4 FCl relates MS (EI): 57 7 (MH ⁺ ).

4- (Diethylamino) but-2-yn-1-yl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindole- 1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.75 (s, 1H), 7.62 ( m, 2H), 7.49 (t, 1H), 7.44 (s, 1H), 7.31 (m, 2H), 7.24 (d, 1H), 7.17 (t, 1H), 6.93 (d, 1H), 4.83 (s, 2H), 3.40 (s, 4H), 2.43 (q, 3H), 1.90 (s, 1H), 0.94 (t _{, 5H); C 30 H 27} N 5 O 4 FCl relates ^{MS (EI): 576 (MH} +).

2- (2-Oxopyrrolidin-1-yl) ethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindole-1 -Yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.90 (t, 1H), 7.64-7.77 (m, 3H), 7 .51 (m, 2H), 7.19-7.35 (m, 3H), 6.96 (t, 1H), 4.27 (q, 2H), 3.46 (m, 5H), 2. 22 (q, 1H), 1.92 (m, 2H); C 28 H 23 N 5 O 5 FCl relates ^{MS (EI): 565 (MH} +).
2- (2,5-Dioxopyrrolidin-1-yl) ethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-iso Indol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.86 (d, 1H), 7.56-7.68 (m, 2H) ), 7.47 (m, 2H), 7.31 (d, 2H), 7.24 (d, 1H), 7.17 (t, 1H), 6.93 (d, 1H), 4.25 (t, 2H), 3.68 ( t, 2H), 2.61 (s, 3H), 1.88 (s, 1H); C 28 H 21 N 5 O 6 FCl relates MS (EI): 577 ( MH ^<+> ).

Cyclobutylmethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Il} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.85 (d, 1 H), 7.71 (s, 1 H), 7.59-7.66 (m, 2 H), 7. 46 (m, 2H), 7.29 (m, 2H), 7.22 (d, 1H), 7.15 (t, 1H), 6.89 (d, 1H), 4.11 (d, 2H) ), 3.40 (d, 1H) , 3.30 (d, 1H), 2.60 (m, 1H), 1.73-1.89 (m, 4H); C 27 H 22 N 4 O 4 MS (EI) for FCl: 521 (MH ^<+> ).

2,2,2-trifluoroethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]- 1H- benzimidazol-2-yl} _{carbamate: C 24 H 15 N 4 O} 4 F 4 Cl about ^{MS (EI): 534 (MH} +).

Ethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.62 (s, 1H), 7.86 (d, 1H), 7.73 (s, 1H), 7.64 (m, 2H), 7. 44 (m, 2H), 7.33 (t, 1H), 7.30 (d, 1H), 7.23 (d, 1H), 7.16 (t, 1H), 6.91 (d, 1H) ), 4.20 (dd, 2H) , 1.25 (t, 1H); C 24 H 18 ClFN 4 O 4 relates ^{MS (EI): 481 (MH} +).

2-Fluoroethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.72 (s, 1H), 7.86 (d, 1H), 7.75 (s, 1H), 7.63 (m, 2H), 7. 49 (m, 1H), 7.45 (s, 1H), 7.33 (t, 1H), 7.30 (d, 1H), 7.24 (d, 1H), 7.17 (t, 1H) ), 6.92 (d, 1H), 4.73 (dd, 1H), 4.61 (dd, 1H), 4.43 (dd, 1H), 4.36 (dd, 1H); C ₂₄ H ₁₇ ClF ₂ N ₄ O ₄ relates ^{MS (EI): 481 (MH} +).

Example 23: Methyl (5-{[2-({[(phenylmethyl) oxy] carbonyl} amino) phenyl] carbonyl} -1H-benzimidazol-2-yl) carbamate: [5- (2-benzylcarbanoyl) A solution of -benzoyl) -1H-benzimidazol-2-yl] -carbamic acid methyl ester (21.4 g, 49.8 mmol) in tetrahydrofuran (150 mL) was cooled in an ice bath. To this solution was added di-tert-butyl dicarbonate (33 g, 150 mmol). To this was then added dropwise a solution of N, N-dimethylaminopyridine (6.1 g, 50 mmole) and Hunig base (8.7 mL, 50 mmol) in tetrahydrofuran (80 mL). The solution was stirred at 0 ^° C. for 40 minutes and then quenched by pouring onto crushed ice and 1N hydrochloric acid (2: 1). The mixture was partitioned and extracted with diethyl ether (200 mL). The organic portion was washed with water, saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, ethyl acetate / hexanes). The isolated product was concentrated in vacuo to give 25 g, 40 mmol (80%) of a colorless oil that was diluted with ethyl acetate (150 mL). To this solution was added a catalytic amount of palladium-carbon (5% wet) and the solution was stirred at room temperature for 18 hours under 1 atmosphere of hydrogen gas. The solution was filtered through celite and concentrated in vacuo to give 24 g, 39 mmol (95%) of a pale yellow oil that was diluted in dichloromethane (150 mL) and cooled to 0 ^° C. To this solution was added pyridine (3.6 ml, 39 mmol), followed by the dropwise addition of cyanuric fluoride (6.6 g, 49 mmol). The solution was stirred at ambient temperature for 3 hours and then quenched by the addition of water (25 mL). The mixture was stirred for 30 minutes at ambient temperature. The mixture was filtered through celite and washed with dichloromethane (2 × 50 mL). The filtrate was partitioned and the organic portion was washed with ice cold 0.5N hydrochloric acid, water and brine, dried over sodium sulfate, and filtered through a silica gel plug column. The product was isolated and concentrated in vacuo to give 16.9 g, 31 mmol (62% over 3 steps) of white solid, which was dissolved in dichloromethane (10 mL) (500 mg, 0.92 mmol). Sodium azide (600 mg, 9.23 mmol) was added to the solution and then stirred at ambient temperature for 15 hours. The mixture was partitioned between water and ethyl acetate. The aqueous portion was extracted twice with ethyl acetate. The organic portions were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 520 mg, 0.92 mmol (100%) of a white solid, which (120 mg, 0.212 mmol) was converted to toluene ( 3 mL). Benzyl alcohol (190 μl, 1.85 mmol) was added to the solution and the solution was stirred at 105 ° C. for 4 hours. The solution was cooled to room temperature and partitioned between water and ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil that was purified by column chromatography (silica gel, 20-40% ethyl acetate in hexanes). The product was isolated and concentrated in vacuo to give 300 mg, 0.46 mmol (50%) of a colorless solid, which was then dissolved in dichloromethane (1 mL). To this solution was added trifluoroacetic acid (100 μl) and the solution was stirred at room temperature for 30 minutes before being partitioned between saturated sodium bicarbonate and dichloromethane. The organic portion was dried over sodium sulfate, washed with brine, filtered and concentrated in vacuo to give a white solid that was recrystallized from ethyl acetate / hexanes. The solid was collected by vacuum filtration and 6 mg, 0.01 mmol (22%) of methyl (5-{[2-({[(phenylmethyl) oxy] carbonyl} amino) phenyl] carbonyl} -1H-benzimidazole-2 -Yl) The carbamate was obtained as a white solid. ¹ H NMR (400 MHz, d ₆ -DMSO): 9.67 (s, 1H), 7.79 (brs, 1H), 7.65-7.62 (m, 1H), 7.58-7. 54 (m, 1H), 7.50-7.43 (m, 3H), 7.30-7.26 (m, 4H), 7.20-7.17 (m, 2H), 4.97 ( _{s, 2H), 3.77 (s} , 3H); C 24 H 20 N 4 O 5 relating ^{MS (EI): 445 (MH} +).

Example 24: Methyl {5-[(2-{[(phenylamino) carbonyl] amino} phenyl) carbonyl] -1H-benzimidazol-2-yl} carbamate: [5- (2-benzylcarbanoyl-benzoyl) A solution of -1H-benzoimidazol-2-yl] -carbamic acid methyl ester (21.4 g, 49.8 mmol) in tetrahydrofuran (150 mL) was cooled in an ice bath. To this solution was added di-tert-butyl dicarbonate (33 g, 150 mmol). To this was then added dropwise a solution of N, N-dimethylaminopyridine (6.1 g, 50 mmole) and Hunig base (8.7 mL, 50 mmol) in tetrahydrofuran (80 mL). The solution was stirred at 0 ^° C. for 40 minutes and then quenched by pouring onto crushed ice and 1N hydrochloric acid (2: 1). The mixture was partitioned and extracted with diethyl ether (200 mL). The organic portion was washed with water, saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, ethyl acetate / hexanes). The isolated product was concentrated in vacuo to give 25 g, 40 mmol (80%) of a colorless oil that was diluted with ethyl acetate (150 mL). To this solution was added a catalytic amount of palladium-carbon (5% wet) and the solution was stirred at room temperature for 18 hours under 1 atmosphere of hydrogen gas. The solution was filtered through celite and concentrated in vacuo to give 24 g, 39 mmol (95%) of a pale yellow oil that was diluted in dichloromethane (150 mL) and cooled to 0 ^° C. To this solution was added pyridine (3.6 ml, 39 mmol), followed by the dropwise addition of cyanuric fluoride (6.6 g, 49 mmol). The solution was stirred at ambient temperature for 3 hours and then quenched by the addition of water (25 mL). The mixture was stirred for 30 minutes at ambient temperature. The mixture was filtered through celite and washed with dichloromethane (2 × 50 mL). The filtrate was partitioned and the organic portion was washed with ice cold 0.5N hydrochloric acid, water and brine, dried over sodium sulfate, and filtered through a silica gel plug column. The product was isolated and concentrated in vacuo to give 16.9 g, 31 mmol (62% over 3 steps) of white solid, which was dissolved in dichloromethane (10 mL) (500 mg, 0.92 mmol). Sodium azide (600 mg, 9.23 mmol) was added to the solution and then stirred at ambient temperature for 15 hours. The mixture was partitioned between water and ethyl acetate. The aqueous portion was extracted twice with ethyl acetate. The organic portions were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 520 mg, 0.92 mmol (100%) of a white solid, which (120 mg, 0.212 mmol) was converted to toluene ( 3 mL). Aniline (30 μl, 0.32 mmol) was added to the solution and the solution was stirred at 105 ° C. for 4 hours. The solution was then cooled to room temperature and partitioned between water and ethyl acetate. The organic portion was washed with 20% aqueous citric acid, brine, sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow residue which was purified by column chromatography (silica gel, 35 in hexanes). % Ethyl acetate). The product was isolated and concentrated in vacuo to give 50 mg, 0.07 mmol of yellow solid, which was immediately dissolved in dichloromethane (2 mL). To this solution was added trifluoroacetic acid (100 μl) and the solution was stirred at room temperature for 20 minutes and then concentrated under reduced pressure to give a yellow solid which was purified by reverse phase HPLC (acetonitrile / water, 0.1% TFA eluent). Purification gave methyl trifluoroacetate {5-[(2-{[(phenylamino) carbonyl] amino} phenyl) carbonyl] -1H-benzimidazol-2-yl} carbamate. ¹ H NMR (400 MHz, d ₆ -DMSO): 10.11 (s, 1H), 7.57-7.37 (m, 4H), 7.25-7.20 (m, 2H), 7.15 −7.02 (m, 3H), 7.02 (d, 3H), 6.83 to 6.80 (m, 1H), 6.76 to 6.75 (m, 1H), 3.83 (s) _{, 3H); C 23 H 19} N 5 O 4 relates ^{MS (EI): 430 (MH} +).

Example 25: Methyl {5- [2- (3-ethynyl-2-fluorophenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl } Carbamate: A solution of 2-[(4-amino-3-nitrophenyl) carbonyl] benzoic acid (10 g, 35 mmol) in DMF (50 mL) was added to cesium carbonate (23 g, 70 mmol) followed by iodomethane (2.2 mL, 35 mmol). Was processed. After the mixture was stirred at room temperature for 1 hour, 50 mL of water was added. A yellow precipitate was formed. The solid was collected by filtration, rinsed with water and dried in vacuo. The desired methyl 2-[(4-amino-3-nitrophenyl) carbonyl] benzoate was obtained as a yellow solid (8.36 g, 27.8 mmol, 80% yield). ¹ H NMR (400 MHz, d ₆ -DMSO): 8.12 (brs, 2H), 8.10 (d, 1H), 7.78-7.75 (m, 2H), 7.70 (m, 1H), 7.48 (dd, 1H ), 7.10 (d, 1H), 3.64 (s, 3H); C 15 H 12 N 2 O 5 related to ^{MS (EI): 323 (MNa} +).

To a solution of 2-[(4-amino-3-nitrophenyl) carbonyl] benzoate (8.36 g, 27.8 mmol) in THF (100 mL) and methanol (30 mL) at 0 ^° C. sodium borohydride (3.0 g). 79 mmol). The mixture was stirred for 40 minutes before the unreacted hydride was quenched with 10% aqueous citric acid. The organic solvent was distilled off under reduced pressure. An orange solid precipitated from the resulting aqueous mixture. This solid was collected by filtration, rinsed with water, triturated with ether and dried in vacuo. The desired 3- (4-amino-3-nitrophenyl) -2-benzofuran-1 (3H) -one was obtained as a light orange solid (5.23 g, 19.4 mmol, 69% yield). ¹ H NMR (400 MHz, d ₆ -DMSO): 8.03 (d, 1H), 7.90 (d, 1H), 7.76 (t, 1H), 7.65-7.60 (m, 3H) ), 7.45 (d, 1H) , 7.11 (dd, 1H), 6.99 (d, 1H), 6.66 (s, 1H); C 14 H 10 N 2 O 4 relates MS (EI ): 303 (MNa ⁺ ).

To a solution of 3- (4-amino-3-nitrophenyl) -2-benzofuran-1 (3H) -one (1.0 g, 3.7 mmol) in NMP (6 mL) was added 3-ethynyl-2-fluoroaniline hydrochloride ( 1.9 g, 11.1 mmol) was added. The mixture was heated to 150 ^° C. for 2.25 hours and then the temperature was raised to 170 ^° C. for an additional 45 minutes. After cooling to room temperature, water and brine were added and the resulting aqueous mixture was extracted twice with ethyl acetate. The organic extract was dried over magnesium sulfate, filtered and preabsorbed on silica gel. The residue was eluted through the column with 60% hexanes and 40% ethyl acetate. Product containing fractions were combined and concentrated. The resulting brown sticky film was not pure. This material was dissolved in acetic acid and to this solution was added tin (II) chloride dihydrate (4.2 g, 18.5 mmol). The mixture was then heated to 80 ^° C. for 1.5 hours. After cooling to room temperature, acetic acid was distilled off under reduced pressure. The residue was transferred to a 500-mL Erlenmeyer flask with a minimal amount of ethyl acetate. The resulting suspension was then diluted with approximately 200 mL of ether before placing the flask in an ice bath. To the vigorously stirred mixture was added 50% aqueous sodium hydroxide (20 mL) and a pale yellow solid was formed. Celite and sodium sulfate were added to adsorb the precipitate and the mixture was dried. The solid was removed by filtration and rinsed twice with hot ethyl acetate. The organic filtrates were combined and concentrated. The crude residue was dissolved in acetic acid (10 mL) and treated with 1,3-bis (methoxycarbonyl) -2-methyl-2-thiopseurea (565 mg, 2.7 mmol) at 80 ^° C. for 25 minutes. After cooling to room temperature, acetic acid was distilled off under reduced pressure. The residue was purified by HPLC. The product-containing fractions were combined and fully saturated sodium bicarbonate was added to pH> 7. The organic solvent was distilled off under reduced pressure, and the resulting aqueous mixture was extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in a minimum amount of ethyl acetate and 1 equivalent of hydrochloric acid (4N in dioxane) was added. A white precipitate formed and was collected by filtration. This material was dried under reduced pressure and methyl hydrochloride {5- [2- (3-ethynyl-2-fluorophenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate (202 mg, 0.46 mmol) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): 7.90 (d, 1H), 7.66-7.57 (m, 3H), 7.67-7.54 (m, 3H), 7.41 (M, 1H), 7.31-7.26 (m, 3H), 7.21 (t, 1H), 6.88 (d, 1H), 6.50 (s, 1H), 4.56 ( _{s, 1H), 3.73 (s} , 3H); C 25 H 17 FN 4 O 3 relates ^{MS (EI): 441 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
Methyl {5- [2- (3-bromophenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz , D ₆ -DMSO): δ 8.07 (m, 1H), 7.88 (d, 1H), 7.67-7.54 (m, 3H), 7.33-7.26 (m, 5H) , 7.01 (br d, 1H) , 6.71 (s, 1H), 3.73 (s, 3H); C 23 H 17 BrN 4 O 3 relates ^{MS (EI): 477,479 (MH} +) .

Example 26: 2- (diethylamino) ethyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] −1H-benzimidazol-2-yl} carbamate: 4-nitrophenyl chloroformate (1.90 g, 9.42 mmol) in diethyl ether (10 mL) at 0 ^° C. with N, N-diethylethanolamine (1 .20 mL, 8.97 mmol) in diethyl ether (5 mL) diluted solution was added. The reaction mixture was immediately warmed to room temperature and stirred for 12 hours. A white precipitate was collected by filtration, washed with diethyl ether, and then dried under reduced pressure to give 2- (diethylamino) ethyl-4-nitrophenyl carbonate hydrochloride (2.3 g, 77%). ¹ H NMR (400 MHz, CDCl ₃ ): 8.28 (d, 2H), 7.43 (d, 2H), 4.86-4.83 (d, 2H), 3.49-3.43 (m , 2H), 3.31-3.15 (br m , 4H), 1.45 (t, 6H); C 13 H 18 N 2 O 5 related to ^{MS (EI): 283 (MH} +).

To a suspension of 2- (diethylamino) ethyl-4-nitrophenyl carbonate hydrochloride (275 mg, 0.862 mmol) and 2-methyl-2-thiopseurea sulfate (120 mg, 0.862 mmol) in acetonitrile (5 mL) was added triethylamine (365 μL). 2.58 mmol) at room temperature. The reaction mixture was heated to 50 ^° C. and stirred for 16 hours, at which point it was concentrated in vacuo. The residue was dissolved with hydrochloric acid (0.5 M, 5 mL) and washed with ethyl acetate. The aqueous layer was basified with sodium bicarbonate powder until pH 7 was reached and chloroform was added. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2- (diethylamino) ethyl [imino (methylthio) methyl] carbamate (102 mg, 50%) as a yellow oil. . _{C 9 H 19 N 3 O 2} S about ^{MS (EI): 234 (MH} +).

2- (3-chloro-2-fluorophenyl) -3- (3,4-diaminophenyl) -3-hydroxy-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.26 mmol) and A solution of 2- (diethylamino) ethyl [imino (methylthio) methyl] carbamate (102 mg, 0.437 mmol) in acetic acid (2.0 mL) was heated to 80 ^° C. and stirred for 25 minutes. The reaction mixture was cooled to room temperature and partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC to give 2- (diethylamino) ethyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindole- 1-yl] -1H-benzimidazol-2-yl} carbamate, trifluoroacetate (29 mg) was obtained. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.85 (d, 1H), 7.75 (s, 1H), 7.67-7.58 (m, 2H), 7.49-7.45. (M, 1H), 7.42 (s, 1H), 7.31-7.27 (m, 2H), 7.23 (d, 1H), 7.15 (t, 1H), 6.90 ( d, 1H), 4.16 (t, 2H), 2.66-2.62 (m, 4H), 2.46 (t, 2H), 1.85 (s, 1H), 0.93 (t _{, 6H); C 28 H 27} ClFN 5 O 4 relates ^{MS (EI): 574 (MNa} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
2-piperidin-1-ylethyl {5- [2- (4-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 -Yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.82 (d, 1H), 7.64 (s, 1H), 7.60-7.55 (m, 2H), 7. 46-7.42 (m, 4H), 7.24 (t, 2H), 7.08 (t, 2H), 6.93 (d, 1H), 4.21 (t, 2H), 2.45 -2.37 (m, 6H), 1.87 (s, 3H), 1.46-1.44 (m, 6H), 1.34 (br m, 2H); C 29 H 28 FN 5 O 4 MS (EI) for: 530 (MH ^<+> ).

2- (Diethylamino) ethyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benz Imidazole-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.85 (d, 1H), 7.75 (s, 1H), 7.67-7.58 (m, 2H) 7.49-7.45 (m, 1H), 7.42 (s, 1H), 7.31-7.27 (m, 2H), 7.23 (d, 1H), 7.15 (t , 1H), 6.90 (d, 1H), 4.16 (t, 2H), 2.66-2.62 (m, 4H), 2.46 (t, 2H), 1.85 (s, _{1H), 0.93 (t, 6H} ); C 28 H 27 ClFN 5 O 4 relates MS (EI): 574 (M a ^+).

2-piperidin-1-ylethyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H- Benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.81 (d, 1H), 7.73 (s, 1H), 7.61-7.54 (m, 2H ), 7.44-7.38 (m, 2H), 7.27-7.22 (m, 2H), 7.19 (d, 1H), 7.11 (t, 1H), 6.85 ( d, 1H), 4.17 (t, 2H), 2.49 (t, 2H), 2.33 (brm, 4H), 1.83 (s, 1H), 1.42-1.39 ( _{m, 4H), 1.29 (br} m, 2H); C 29 H 27 ClFN 5 O 4 MS (EI) for 586 ^(MNa +).

2- [Methyl (phenylmethyl) amino] ethyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl ] -1H-benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.81 (s, 1H), 7.69-7.60 (M, 2H), 7.55-7.52 (m, 2H), 7.47-7.46 (m, 5H), 7.35 (t, 1H), 7.29-7.18 (m , 2H), 7.20 (t, 1H), 6.99 (d, 1H), 4.52 (brs, 2H), 4.39 (brs, 2H), 3.45 (brs, 2H) _{), 2.75 (s, 3H)} ; C 32 H 27 ClFN 5 O 4 relates MS (EI): 6 0 ^(MH +).

2- (Dimethylamino) ethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H- Benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.87 (d, 1H), 7.73 (s, 1H), 7.64 (m, 2H), 7. 49 (t, 1H), 7.44 (roads, 1H), 7.33 (d, 1H), 7.31 (d, 1H), 7.24 (d, 1H), 7.17 (t, 1H), 6.91 (d, 1H ), 4.23 (t, 2H), 2.55 (t, 2H), 2.21 (s, 6H); C 26 H 23 N 5 O 4 ClF relates MS (EI): 524 (MH ^<+> ).

2-morpholin-4-ylethyl {6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H- Benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.88 (d, 1H), 7.82 (s, 1H), 7.64 (m, 2H), 7. 50 (m, 2H), 7.26-7.36 (m, 3H), 7.17 (m, 1H), 7.01 (m, 1H), 4.49 (t, 1H), 4.44 (t, 1H), 4.33 ( t, 1H), 3.71-3.97 (m, 3H), 3.20-3.48 (m, 6H); C 28 H 25 N 5 O 5 FCl MS (EI) for: 566 (MH ^<+> ).

2-piperidin-1-ylethyl {6- [2- (3-bromophenyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate . ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.56 (s, 1H), 8.07 (d, 1H), 7.87 (d, 1H), 7.65 (m, 2H), 7. 60 (d, 1H), 7.55 (t, 1H), 7.27 (m, 4H), 6.95 (d, 1H), 6.69 (s, 1H), 4.23 (t, 2H) ), 3.35 (s, 2H), 2.54 (t, 1H), 2.38 (br.s, 1H), 1.46 (m, 4H), 1.35 (m, 1H); C ₂₉ H ₂₈ BrN ₅ O ₃ relates ^{MS (EI): 575 (MH} +).

Example 27: Methyl [6-({2-[(phenylcarbonyl) amino] phenyl} carbonyl) -1H-benzimidazol-2-yl] carbamate: [5- (2-benzylcarbanoyl-benzoyl) -1H- A solution of benzimidazol-2-yl] -carbamic acid methyl ester (21.4 g, 49.8 mmol) in tetrahydrofuran (150 mL) was cooled in an ice bath. To this solution was added di-tert-butyl dicarbonate (33 g, 150 mmol). To this was then added dropwise a solution of N, N-dimethylaminopyridine (6.1 g, 50 mmole) and Hunig base (8.7 mL, 50 mmol) in tetrahydrofuran (80 mL). The solution was stirred at 0 ^° C. for 40 minutes and then quenched by pouring onto crushed ice and 1N hydrochloric acid (2: 1). The mixture was partitioned and extracted with diethyl ether (200 mL). The organic portion was washed with water, saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, ethyl acetate / hexanes). The isolated product was concentrated in vacuo to give 25 g, 40 mmol (80%) of a colorless oil that was diluted with ethyl acetate (150 mL). To this solution was added a catalytic amount of palladium-carbon (5% wet) and the solution was stirred at room temperature for 18 hours under 1 atmosphere of hydrogen gas. The solution was filtered through celite and concentrated in vacuo to give 24 g, 39 mmol (95%) of a pale yellow oil that was diluted in dichloromethane (150 mL) and cooled to 0 ^° C. To this solution was added pyridine (3.6 ml, 39 mmol), followed by the dropwise addition of cyanuric fluoride (6.6 g, 49 mmol). The solution was stirred at ambient temperature for 3 hours and then quenched by the addition of water (25 mL). The mixture was stirred for 30 minutes at ambient temperature. The mixture was filtered through celite and washed with dichloromethane (2 × 50 mL). The filtrate was partitioned and the organic portion was washed with ice cold 0.5N hydrochloric acid, water and brine, dried over sodium sulfate, and filtered through a silica gel plug column. The product was isolated and concentrated in vacuo to give 16.9 g, 31 mmol (62% over 3 steps) of a white solid, of which 500 mg, 0.92 mmol was dissolved in dichloromethane (15 mL). Sodium azide (600 mg, 9.23 mmol) was added to this solution. The mixture was stirred at room temperature for 15 hours and then partitioned between water and ethyl acetate. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 520 mg, 0.92 mmol (100%) of a white solid, which was dissolved in toluene (10 mL). Benzyl alcohol (190 μl, 1.84 mmol) was added to this solution. The solution was stirred at 105 ° C. for 4 hours before the solution was cooled to room temperature and partitioned between water and ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil that was purified by column chromatography (silica gel, 20-40% ethyl acetate in hexanes). The product was collected to give 300 mg, 0.47 mmol (50%) of a colorless oil that was diluted with ethyl acetate (5 mL). To this solution was added palladium (5% by weight (dry base) with respect to the wet activated carbon), and the solution was stirred at room temperature for 3 hours under a hydrogen gas filled balloon (1 atm). The mixture was filtered and the filtrate was concentrated in vacuo to give 194 mg, 0.38 mmol (95%) of a light yellow solid. This solid was dissolved in 1,2-dichloroethane (2 mL). To this solution was added benzoyl chloride (7 μl, 0.06 mmol) and the solution was stirred at room temperature for 30 minutes. To this solution was added trifluoroacetic acid (300 μl) and the solution was stirred at room temperature for an additional 30 minutes. The solution was then concentrated under reduced pressure to give an orange residue which was purified by reverse phase HPLC (acetonitrile / water, 0.1% TFA eluent). The product was collected and 20.2 mg, 0.04 mmol (4% over 5 steps) of methyl trifluoroacetate [6-({2-[(phenylcarbonyl) amino] phenyl} carbonyl) -1H-benzimidazole-2 -Yl] carbamate was obtained as a white solid. ¹ H NMR (400 MHz, d ₆ -DMSO): 10.68 (s, 1H), 7.88-7.86 (m, 2H), 7.70 (d, 2H), 7.66-7.58 (M, 2H), 7.55-7.48 (m, 3H), 7.46-7.42 (m, 2H), 7.35-7.31 (m, 1H), 3.80 (s _{, 3H); C 23 H 18} N 4 O 4 relates ^{MS (EI): 414 (MH} +).

Example 28: Methyl {5- [2- (3-ethynyl-2-fluorophenyl) -4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl ] -1H-benzimidazol-2-yl} carbamate: To a solution of 3,6-difluorophthalic anhydride (3.0 g, 16.00 mmol) in 1,1,2,2-tetrachloroethane (30 mL), chlorobenzene ( 2.0 mL, 18.00 mmol) was added followed by aluminum chloride (4.40 g, 33.00 mmol). The reaction mixture was stirred at room temperature for 120 minutes and then stirred at 60 ^° C. for an additional 90 minutes. This was cooled to room temperature, poured into ice water (300 mL) and diluted with 1M hydrochloric acid. The aqueous slurry was extracted with ethyl acetate (300 mL) and the organic layer was washed with water (70 mL), brine (70 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude product which was crystallized from ethyl acetate by addition of hexane. The product was collected by filtration and dried under reduced pressure to give 2-[(4-chlorophenyl) carbonyl] -3,6-difluorobenzoic acid (3.52 g, 73% yield). ¹ HMR (400 MHz, CD ₃ OD): 7.77 (s, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.53- 7.34 (m, 2H). MS about _{C 14 H 7 ClF 2 O 3} (EI): 281 (M-H 2 O).

2-[(4-Chlorophenyl) carbonyl] -3,6-difluorobenzoic acid (3.20 g, 11.00 mmol) was dissolved with heating in concentrated sulfuric acid (15 ml) and cooled to 0 ^° C. Fuming nitric acid (0.5 ml, 11.00 mmol) solution in concentrated sulfuric acid (3.0 mL) was added dropwise and the reaction mixture was stirred at 0 ^° C. for 60 min. This was poured into crushed ice. The product precipitated. This was collected by filtration and then dissolved in ethyl acetate (100 mL); washed with water (2 × 40 mL), brine (40 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude product which was triturated with hexane. The crystalline product was collected by filtration to give 2-[(4-chloro-3-nitrophenyl) carbonyl] -3,6-difluorobenzoic acid (2.73 g, 74% yield). ¹ H NMR (400 MHz, CD ₃ OD): 8.28 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), _{7.53-7.42 (m, 2H); C} 14 H 7 ClF 2 NO 5 relates ^{MS (EI): 341 (M} -).

To a solution of 2-[(4-chloro-3-nitrophenyl) carbonyl] -3,6-difluorobenzoic acid (7.0 g, 22.00 mmol) in dichloroethane anhydride (40 mL) at 0 ^° C. with pyridine (1.70 ml). 22.00 mmol) was added followed by cyanuric fluoride (1.90 ml, 24.20 mmol). The reaction mixture was stirred at 0 ° C. for 120 minutes. Water (35 mL) was added to the reaction mixture and stirred at 0 ^° C. for 10 minutes. The resulting slurry was filtered through a celite pad and washed with dichloromethane. The filtrate was partitioned with water and the organic layer was washed with water. This was dried over anhydrous sodium sulfate. Filtration and concentration gave a crystalline product. This was collected by filtration and dried under reduced pressure to give 3- (4-chloro-3-nitrophenyl) -3,4,7-trifluoro-2-benzofuran-1 (3H) -one (5.77 g, 82% yield). Rate). MS about _{C 14 H 5 ClF 3 NO 4} (EI): 342 (M -).

3- (4-Chloro-3-nitrophenyl) -3,4,7-trifluoro-2-benzofuran-1 (3H) -one (2.70 g, 7.85 mmol) of 1,2-dichloroethane (30. To the 0 mL) solution was added 2-fluoro-3-alkyneaniline (1.11 g, 8.25 mmol) followed by N, N-dimethylaniline (1.20 mL, 9.42 mmol). The reaction mixture was stirred at 75 ^° C. for 15 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (350 mL). Washed with 1M hydrochloric acid (2 × 100 mL), water (3 × 100 mL), saturated sodium bicarbonate (100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave a semi-solid residue that was crystallized from diethyl ether by addition of hexane. The product was collected by filtration and dried under reduced pressure to give 3- (4-chloro-3-nitrophenyl) -2- (3-ethynyl-2-fluorophenyl) -4,7-difluoro-3-hydroxy-2,3 -Dihydro-1H-isoindol-1-one (2.47 g, 68% yield) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): 8.01 (s, 1H), 7.60 (s, 2H), 7.51-7.42 (m, 3H), 7.32 (t, J = 6.4 Hz, 1 H), 7.15 (t, J = 8 Hz, 1 H), 3.80 (s, 1 H); MS (EI) for C ₂₂ H ₁₀ ClF ₃ N ₂ O ₄ : 459 (MH ⁺ ) .

3- (4-Chloro-3-nitrophenyl) -2- (3-ethynyl-2-fluorophenyl) -4,7-difluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one To a solution of (2.45 g, 5.34 mmol) in N, N-dimethylformamide (30.0 mL) was added sodium azide (1.05 g, 16.0 mmol) and the reaction mixture was stirred at 40 ^° C. for 20 hours. . The reaction mixture was cooled to room temperature and poured into ice water. A precipitate formed and was collected by filtration. This was washed with water and dried under reduced pressure to give 3- (4-azido-3-nitrophenyl) -2- (3-ethynyl-2-fluorophenyl) -4,7-difluoro-3-hydroxy-2,3-dihydro. -1H-isoindol-1-one (1.87 g, 75% yield) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): 8.00 (d, J = 2 Hz, 1H), 7.64 (dd, J ₁ = 8.4 Hz, J ₂ = 1.6 Hz, 1H), 7.47 −7.41 (m, 4H), 7.35 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 8 Hz, 1H), 3.80 (s, 1H); C ₂₂ H ₁₀ F ₃ N ₅ O ₄ relates ^{MS (EI): 464 (M} -).

In a mixture of tetrahydrofuran-water (1: 1, 30.0 mL), 3- (4-azido-3-nitrophenyl) -2- (3-ethynyl-2-fluorophenyl) -4,7-difluoro-3- To a solution of hydroxy-2,3-dihydro-1H-isoindol-1-one (1.50 mg, 3.20 mmol) was added ammonium formate (2.0 g, 32.0 mmol) followed by iron (1.45 g, 26.0 mmol) was added. The mixture was heated to reflux and stirred for 180 minutes. This was cooled to room temperature and diluted with ethyl acetate. The resulting slurry was filtered through a celite pad and washed with ethyl acetate. This was partitioned with water and the organic layer was washed with water, brine and dried over anhydrous sodium sulfate. Filtration and concentration gave an oily product. This was crystallized from diethyl ether by the addition of hexane. The product was collected by filtration and dried in vacuo to give 3- (3,4-diaminophenyl) -2- (3-ethynyl-2-fluorophenyl) -4,7-difluoro-3-hydroxy-2,3-dihydro. -1H-isoindol-1-one (1.16 g, 88% yield) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): 7.57 (s, 1H), 7.42-7.23 (m, 3H), 7.16 (m, 2H), 6.75 (s, 1H) , 6.61-6.57 (m, 1H), 3.78 (d, J = 8.4Hz, 1H); C 22 H 14 F 3 N 3 O 2 relates MS (EI): 408 (M -) .

3- (3,4-Diaminophenyl) -2- (3-ethynyl-2-fluorophenyl) -4,7-difluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (1 .15 g, 2.80 mmol) and 1,3-bis (methoxycarbonyl) -2-methyl-2-thiopseurea (0.58 g, 2.80 mmol) in glacial acetic acid (15.0 mL) were added to 80 ^° C. Heated for 30 minutes. The reaction mixture was cooled to room temperature and poured into ice water. The pH was adjusted to 8 by addition of 2M aqueous sodium hydroxide. The precipitated product was extracted with ethyl acetate (350 mL) and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude product. This was purified by reverse phase preparative HPLC (CH ₃ CN / 25 mM aqueous ammonium acetate). Fractions were collected and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. Filtration and concentration gave an amorphous residue which was lyophilized from a mixture of acetonitrile-water (35.0 mL) to give methyl {5- [2- (3-ethynyl-2-fluorophenyl) -4,7 -Difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} carbamate (1.15 g, 83% yield) was obtained. . ¹ H NMR (400 MHz, CD ₃ OD): 7.79 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.43-7.36 (m, 4H), 7. 31 (t, J = 7.2 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 3.92 (s, 3H), 3.78 (s, 1H); C ₂₅ H ₁₅ F ₃ N ₄ O ₄ relates ^{MS (EI): 493 (MH} +).

The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
Methyl hydrochloride {6- [4,7-dichloro-2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H -Benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.03-8.02 (b, 1H), 7.71 (s, 2H), 7.53-7. 49 (m, 1H), 7.38-7.36 (d, 1H), 7.22-7.15 (m, 3H), 3.78 (s, 3H); C 23 H 14 Cl 3 FN 4 O ₄ on ^{MS (EI): 535 (MH} +).

Methyl hydrochloride {6- [2- (3-bromophenyl) -4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.29 (s, 0.8 H) close, 7.88 (s, 0.2 H) open, 7.78-7.76 ( m, 1H), 7.70-7.60 (m, 1H), 7.53-7.20 (m, 7H), 3.82 (s, 2.4H) close, 3.78 (s, 0 _{.6H) open; C 23 H 15} BrF 2 N 4 O 4 relates ^{MS (EI): 529 (MH} +).

Methyl {6- [2- (5-chloro-2-methylphenyl) -4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H- Benzimidazol-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.28 (s, 0.3 H) open, 7.88-7.83 (m, 1 H), 7.65- 7.57 (m, 3H), 7.37-7.19 (m, 2.4H), 7.15-7.07 (m, 1H), 6.90-6.82 (m, 1H), 5.9-5.97 (b, 0.3 H) open, 3.78 (s, 0.9 H) open, 3.73 (s, 2.1 H) close, 2.10 (s, 0.9 H) open, 1.45 (s, 2.1 H) close; C ₂₄ H ₁₇ ClF ₂ N ₄ O MS (EI) for ₄ : 499 (MH ^<+> ).

Methyl hydrochloride {6- [2- (3-chloro-2-fluorophenyl) -7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benz Imidazole-2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.22-8.20 (b, 1H), 7.77-7.75 (d, 1H), 7.72- 7.68 (m, 1H), 7.64-7.62 (b, 1H), 7.53-7.44 (m, 3H), 7.32-7.29 (dd, 1H), 7. _{20-7.16 (dd, 2H), 3.81} (s, 3H); C 23 H 15 ClF 2 N 4 O 4 relates ^{MS (EI): 485 (MH} +).

Methyl {6- [2- (3-bromophenyl) -5,6-dichloro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole-2 - yl} carbamate, trifluoroacetic acid _{salt: C 23 H 15 N 4 O} 4 Cl 2 Br about the ^{MS (EI): 563 (MH} +).

Methyl {5- [2- (3-ethynyl-2-fluorophenyl) -7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole -2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.94 (s, 1H), 7.75 (d, 1H), 7.67-7.72 (m, 1H), 7.43-7.50 (m, 4H), 7.32 (t, 1H), 7.25 (d, 1H), 7.14 (t, 1H), 6.94 (d, 1H), 4 MS (EI) for C ₂₅ H ₁₆ N ₄ O ₄ F ₂ : 475 (MH ⁺ ) .51 (s, 1H), 3.73 (s, 3H);

Methyl {5- [2- (5-chloro-2-methylphenyl) -7-fluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole -2-yl} carbamate: ¹ H NMR (400 MHz, d ₆ -DMSO): 11.64 (broad s, 1H), 7.54 (s, 2H), 7.46-7.62 (m, 2H) 7.16-7.26 (m, 2H), 7.07 (d, 1H), 6.77 (d, 1H), 3.77 (s, 0.6H) open, 3.72 (s, _{2.4H) close, 3.35 (s,} 3H); C 24 H 18 N 4 O 4 FCl relates ^{MS (EI): 481 (MH} +).

Methyl {6- [2- (3-chloro-2-fluorophenyl) -4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H- Benzimidazol-2-yl} carbamate. ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.60 (br.s, 1H), 8.06 (s, 1H), 7.63 (m, 1H) open, 7.53 (m, 4H) 7.38 (t, 1H) open, 7.25 (m, 2H), 7.17 (m, 1H), 7.14 (t, 1H) open, 6.97 (d, 1H), 3. 77 (s, 3H) open, 3.73 (s, 3H) close; C 23 H 14 ClF 3 N 4 O 4 relates ^{MS (EI): 503 (MH} +).

Example 29: 5- [2- (3-Chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1,3-dihydro- 2H-benzimidazol-2-one: 2- (3-chloro-2-fluorophenyl) -3- (3,4-diaminophenyl) -3-hydroxy-2,3-dihydro-1H-isoindole-1- To a solution of ON (100 mg, 0.26 mmol) in tetrahydrofuran (3 mL) was added 1,1′-carbonyldiimidazole (63 mg, 0.39 mmol) at room temperature. The reaction mixture was stirred for 2 hours at which time the solvent was evaporated. The residue was purified by reverse phase HPLC to give 5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1 , 3-Dihydro-2H-benzimidazol-2-one (34 mg) was obtained. ¹ H NMR (400 MHz, d ₆ -DMSO): 10.63 (s, 1H), 10.52 (s, 1H), 7.84 (d, 1H), 7.72 (d, 1H), 7. 68-7.58 (m, 2H), 7.50 (dt, 1H), 7.31-7.29 (m, 2H), 7.19 (t, 1H), 6.84-6.77 ( _{m, 3H); C 21 H} 13 ClFN 3 O 3 relates ^{MS (EI): 408 (MH} -).

Example 30: Methyl {6- [1- (3-bromophenyl) -5-oxopyrrolidin-2-yl] -1H-benzimidazol-2-yl} carbamate: 3,4-dinitrobenzaldehyde (634.5 mg, 3.24 mmol) was dissolved in dichloromethane (20 mL) and the resulting solution was cooled to 0 ^° C. under a nitrogen atmosphere. [(1-Ethoxycyclopropyl) oxy] trimethylsilane (0.85 mL, 4.21 mmol) was added by syringe, followed by titanium tetrachloride (0.4 mL, 3.56 mmol) and the resulting mixture was stirred for 12 hours. The mixture was slowly warmed to room temperature and stirred for another 3 days. The solution was partitioned between water and the organic layer was dried over anhydrous sodium sulfate. Filtration and concentration followed by purification of the residue using silica gel flash chromatography (1: 1 to 3: 1 ethyl acetate: hexane eluent) gave a less polar fraction, ethyl 4-chloro-4- (3,4-dinitro Phenyl) butanoate (379 mg, 37% yield) as an amorphous residue and 5- (3,4-dinitrophenyl) dihydrofuran-2 (3H) -one as a more polar fraction (338 mg, 41% yield). Rate). ¹ H NMR (400 MHz, CDCl ₃ ): 7.98 (d, 1H), 7.96 (d, 1H), 7.80 (dd, 1H), 5.11 (dd, 1H), 4.15 ( q, 2H), 2.66-2.50 (m, 2H), 2.42-2.28 (m, 2H), 1.27 (tr, 3H).

Ethyl 4-chloro-4- (3,4-dinitrophenyl) butanone (366.3 mg, 1.2 mmol), 3-bromoaniline (220 mg, 1.3 mmol.) And N, N-dimethylacetamide (0.3 mL) And heated to 120 ^° C. under a nitrogen atmosphere for 17 hours. The mixture was then cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed twice more with water, brine and then dried over anhydrous sodium sulfate. Filtration and concentration followed by purification of the residue by silica gel flash chromatography (100% ethyl acetate eluent) gave 1- (3-bromophenyl) -5- (3,4-dinitrophenyl) pyrrolidin-2-one (132 mg 28% yield) as an amorphous residue. The material thus obtained was contaminated with various amounts of 5- (3,4-dinitrophenyl) dihydrofuran-2 (3H) -one as a by-product and proceeded without further purification. _{C 16 H 12 N 3 O 5} Br relates ^{MS (EI): 407 (MH} +).

1- (3-Bromophenyl) -5- (3,4-dinitrophenyl) pyrrolidin-2-one (132 mg, 0.33 mmol) was dissolved in acetic acid (5.0 mL) and the resulting solution was brought to 50 ^° C. Warm, then tin (II) chloride dihydrate (368 mg, 1.65 mmol.) Was added. After 1 hour at 50 ^° C., a second aliquot of tin (II) chloride dihydrate was added and heating was continued for an additional 3 hours. The resulting solution was concentrated and the residue was partitioned between ethyl acetate and 1M aqueous sodium hydroxide. The organic layer was separated from the resulting emulsion and further washed with saturated sodium bicarbonate solution followed by brine. The solution was then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography (100% ethyl acetate eluent) to give 1- (3-bromophenyl) -5- (3,4-aminophenyl) pyrrolidin-2-one (16.4 mg, 15% yield). Rate) as an amorphous residue. _{C 16 H 16 N 3 O 3} Br relates ^{MS (EI): 347 (MH} +).

1- (3-Bromophenyl) -5- (3,4-aminophenyl) pyrrolidin-2-one (16.4 mg, 0.05 mmol.) Was dissolved in acetic acid (1.0 mL) and then 1,3-bis (Methoxycarbonyl) -2-methyl-2-thiopseurea (14.5 mg, 0.07 mmol.) Was added and the mixture was heated to 80 ^° C. for 1 hour. The solution was then concentrated and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was washed once with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography (100% ethyl acetate eluent) to give methyl {6- [1- (3-bromophenyl) -5-oxopyrrolidin-2-yl] -1H-benzimidazol-2-yl. } Obtained the carbamate (12.9 mg, 64% yield) as a white solid. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.82 (s, 1H), 7.36-7.30 (m, 2H), 7.27 (s, 1H), 7.22-7.16 (M, 2H), 7.00 (d, 1H), 5.53 (tr, 1H), 3.73 (s, 3H), 2.70-2.50 (m, 4H). _{C 19 H 17 N 4 O 3} Br relates ^{MS (EI): 430 (MH} +).

Example 31: Methyl ({6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benz Imidazol-2-yl} amino) (oxo) acetate: suspension of 2-methyl-2-thiopseurea sulfate (1.50 g, 10.80 mmol) in dichloromethane (50 mL) and pyridine (1.76 mL, 21.60 mmol). To the suspension was added a solution of methyl chlorooxoacetate (1.0 mL, 10.80 mmol) in dichloromethane (10.0 mL) at 0 ^° C., and the reaction mixture was stirred at room temperature for 15 hours. Ethyl acetate (150 mL) was added to the mixture and washed with 1M hydrochloric acid and brine. The solvent was dried over anhydrous sodium sulfate. Filtration and concentration followed by purification of the crude by flash chromatography on silica gel (hexane: ethyl acetate 4: 3 to 3: 2 eluent) gave methyl {[(1Z)-{[(methyloxy) (oxo) acetyl] Amino} (methylthio) methylidene] amino} (oxo) acetate (0.87 g, 31% yield) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ): 12.48 (br.s, 2H), 3.81 (s, 3H), 2.41 (s, 3H); C ₈ H ₁₀ N ₂ O ₆ S MS (EI) for: 263 (MH ^<+> ).

2- (3-Chloro-2-fluorophenyl) -3- (3,4-diaminophenyl) -3-hydroxy-2,3-dihydro-1H-isoindol-1-one (0.10 g, 0.26 mmol) ) And methyl {[(1Z)-{[(methyloxy) (oxo) acetyl] amino} (methylthio) methylidene] amino} (oxo) acetate (67 mg, 0.26 mmol) in n-butanol (2.0 mL) ^Was heated to 80 ^° C. for 5 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The resulting crude was purified by reverse phase preparative HPLC (CH ₃ CN / 25 mM aqueous ammonium acetate). Fractions were collected and the solvent was concentrated. The aqueous residue was partitioned with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. Filtration and concentration gave an oily residue which was lyophilized from a mixture of acetonitrile-water (5.0 mL) and methyl ({6- [2- (3-chloro-2-fluorophenyl) -1-hydroxy- 3-Oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazol-2-yl} amino) (oxo) acetate (48 mg, 38% yield) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ): 11.86 (d, 1H), 7.87 (d, 1H), 7.65 (m, 2H), 7.53 (t, 1H), 7. 33 (t, 1H), 7.30 (d, 1H), 7.25 (s, 1H), 7.20 (t, 1H), 6.99 (d, 1H), 6.91 (d, 1H) ), 3.57 (s, 3H); ¹³ C NMR (400 MHz, DMSO-d ₆ ): 67.0, 92.5, 110.0, 113.8, 114.1, 115.7, 120.8 121.4, 123.9, 125.3, 125.6, 126.0, 126.2, 129.5, 129.8, 130.5, 130.7, 134.3, 134.8, 150 .3, 155.7, 155.8, 163.5, 166.2; MS for C ₂₄ H ₁₆ ClFN ₄ O _{4 (EI): 436 (M-} CO 2 CH 3).

Example 32: 2- (3-Chloro-2-fluorophenyl) -3-hydroxy-3- [2- (1,3-thiazol-2-ylamino) -1H-benzimidazol-5-yl] -2, To a solution of 3-dihydro-1H-isoindol-1-one: 2-aminothiazole (630 mg, 6.29 mmol) in acetone (30 mL) was slowly added benzoyl isothiocyanate (845 μL, 6.29 mmol) at room temperature. The reaction mixture was heated to gently reflux for 6.5 hours, at which point it was cooled to room temperature and concentrated in vacuo. Acetonitrile (50 mL) was added to the residue, and the yellow precipitate was filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 10% sodium hydroxide (50 mL). The heterogeneous reaction mixture was heated to reflux slowly for 1 hour, cooled to room temperature and stirred for 16 hours. To the reaction mixture was added 6N hydrochloric acid until pH 7 was reached. Aqueous ammonium hydroxide solution (50 mL) and then ethyl acetate were added to the aqueous layer, followed by separation. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give N-1,3-thiazol-2-ylthiourea (717 mg, 71%) as a pale yellow powder. The powder was then dissolved in chloroform (50 mL) and iodomethane (281 μL, 4.50 mmol) was added to the suspension. The reaction mixture was heated to reflux for 2 hours, at which time it was cooled to room temperature and concentrated in vacuo. The residue was obtained by column chromatography (SiO _2, hexanes / ethyl acetate) to give methyl N-1,3-thiazol-2-yl imide thiocarbamate (200 mg, 26%). C ₅ H ₇ N ₃ S ₂ relating ^{MS (EI): 174 (MH} +).

2- (3-chloro-2-fluorophenyl) -3- (3,4-diaminophenyl) -3-hydroxy-2,3-dihydro-1H-isoindol-1-one (30 mg, 0.078 mmol) and A solution of methyl N-1,3-thiazol-2-ylimidothiocarbamate (200 mg, 1.15 mmol) in acetic acid (1.5 mL) was heated to 80 ^° C. and stirred for 1 hour. The reaction mixture was cooled to room temperature and partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, then dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC to give 2- (3-chloro-2-fluorophenyl) -3-hydroxy-3- [2- (1,3-thiazol-2-ylamino) -1H-benzimidazole-5- Yl] -2,3-dihydro-1H-isoindol-1-one, trifluoroacetate (6.6 mg). ¹ H NMR (400 MHz, d ₆ -DMSO): 8.02 (d, 0.5 H), 7.86 (d, 1 H), 7.73 (s, 1 H), 7.66-7.61 (m , 3H), 7.52-7.47 (m, 2H), 7.35-7.27 (m, 4H), 7.21-7.15 (m, 2H), 6.92 (br s, _{1H); C 24 H 15 ClFN} 5 O 2 S about ^{MS (EI): 492 (MH} +).
The following compounds of the invention were prepared using the same or similar synthetic methods and / or instead of other reagents:
3- (2-{[4,6-Bis (methyloxy) pyrimidin-2-yl] amino} -1H-benzimidazol-5-yl) -2- (3-chloro-2-fluorophenyl) -3- Hydroxy-2,3-dihydro-1H-isoindol-1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.52 (s, 1H), 7.89 (d, 1H), 7.79 (S, 1H), 7.65 (m, 2H), 7.51 (m, 2H), 7.34 (m, 3H), 7.18 (t, 1H) closed, 7.12 (t, 1H) ) Open, 6.99 (d, 1H), 5.89 (s, 1H) open, 5.88 (s, 1H) closed, 3.95 (s, 6H) open, 3.94 (s, 6H) _{closed; C 27 H 20 ClFN 6} O 4 MS (EI) for 547 ^(MH +).

2- (3-Chloro-2-fluorophenyl) -3-hydroxy-3- (2-{[4-methyl-6- (methyloxy) pyrimidin-2-yl] amino} -1H-benzimidazole-5 Yl) -2,3-dihydro-1H-isoindol-1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 10.54 (s, 1 H), 7.88 (d, 1 H), 7. 76 (s, 1H), 7.66 (m, 2H), 7.50 (m, 2H), 7.33 (m, 3H), 7.17 (t, 1H), 6.96 (d, 1H) ), 6.41 (s, 1H) open, 6.37 (s, 1H) closed, 3.94 (s, 3H), 2.44 (s, 3H) open, 2.41 (s, 3H) closed ; MS about _{C 27 H 20 ClFN 6 O 3} (EI): 531 (MH + ).

2- (3-Chloro-2-fluorophenyl) -3-hydroxy-3- [2- (pyridin-2-ylamino) -1H-benzimidazol-5-yl] -2,3-dihydro-1H-isoindole -1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.29 (s, 1H), 7.88 (d, 1H), 7.73-7.47 (m, 4H), 7. 49 (t, 2H), 7.33-7.31 (m, 3H), 7.19-7.15 (m, 2H), 6.98 (s, 1H); C 26 H 17 ClFN 5 O 2 MS (EI) for: 486 (MH ^<+> ).

2- (3-Chloro-2-fluorophenyl) -3-hydroxy-3- [2- (pyrimidin-2-ylamino) -1H-benzimidazol-5-yl] -2,3-dihydro-1H-isoindole -1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.59-8.58 (m, 2H), 7.87 (dd, 1H), 7.70 (s, 1H), 7. 66-7.61 (m, 2H), 7.48 (br m, 2H), 7.33-7.31 (m, 4H), 7.18-7.16 (m, 1H), 7.04 -7.02 (m, 1H), 6.94 (br s, 1H); C 25 H 16 ClFN 6 O 2 relates ^{MS (EI): 487 (MH} +).

2- (3-Chloro-2-fluorophenyl) -3-hydroxy-3- [2- (1,3-thiazol-2-ylamino) -1H-benzimidazol-5-yl] -2,3-dihydro- 1H-isoindol-1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.02 (d, 0.5 H), 7.86 (d, 1 H), 7.73 (s, 1 H), 7.66-7.61 (m, 3H), 7.52-7.47 (m, 2H), 7.35-7.27 (m, 4H), 7.21-7.15 (m, 2H) ), 6.92 (br s, 1 H); MS (EI) for C ₂₄ H ₁₅ ClFN ₅ O ₂ S: 492 (MH ⁺ ).

2- (3-Chloro-2-fluorophenyl) -3-hydroxy-3- [2- (pyrazin-2-ylamino) -1H-benzimidazol-5-yl] -2,3-dihydro-1H-isoindole -1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.57 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.88 (d, 1H), 7.72 (s, 1H), 7.69-7.60 (m, 3H), 7.49 (t, 1H), 7.32 (d, 2H), 7.17 (t, 1H) _{), 6.95 (s, 1H)} ; C 25 H 16 ClFN 6 O 2 relates ^{MS (EI): 487 (MH} +).

2- (3-Ethynyl-2-fluorophenyl) -3-hydroxy-3- [2- (pyrimidin-2-ylamino) -1H-benzimidazol-5-yl] -2,3-dihydro-1H-isoindole -1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 12.17 (s, 1H), 11.18 (s, 1H), 8.62-8.57 (m, 2H), 7. 87 (d, 1H), 7.69-7.59 (m, 3H), 7.43 (t, 2H), 7.41-7.34 (m, 1H), 7.32 (d, 1H) , 7.14 (t, 1H), 7.04 (t, 1H), 6.94 (br s, 1H), 4.49 (s, 1H); C 27 H 17 FN 6 O 2 relates MS EI) : 477 (MH ^<+> ).

2- (3-Chloro-2-fluorophenyl) -3- {2-[(6-chloropyridazin-3-yl) amino] -1H-benzimidazol-5-yl} -3-hydroxy-2,3- dihydro -1H- _{isoindol-1-: C 25 H 15 Cl 2 FN} 6 O 2 relates ^{MS (EI): 521 (M} +).

2- (3-Chloro-2-fluorophenyl) -3- {2-[(5-chloropyrimidin-2-yl) amino] -1H-benzimidazol-5-yl} -3-hydroxy-2,3- Dihydro-1H-isoindol-1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.79-8.74 (m, 2H), 7.92-7.85 (m, 2H), 7 .71-7.61 (m, 3H), 7.59-7.56 (m, 1H), 7.53-7.46 (m, 1H), 7.44-7.40 (m, 1H) , 7.38-7.30 (m, 3H), 7.23-7.17 (m, 1H), 7.14-7.09 (m, 1H); C 25 H 15 Cl 2 FN 6 O 2 MS (EI) for: 521 (M ^<+> ).

3-Hydroxy-2- (3-methylphenyl) -3- [2- (pyrimidin-2-ylamino) -1H-benzimidazol-6-yl] -2,3-dihydro-1H-isoindol-1-one : ¹ H NMR (400 MHz, d ₆ -DMSO): 8.60 (d, 2H), 7.82 (d, 1H), 7.57 (m, 5H), 7.43 (s, 1H), 7 .28 (m, 3H), 7.11 (t, 1H), 7.04 (t, 1H), 6.91 (d, 1H), 2.20 (s, 3H); C ₂₆ H ₂₀ N ₆ O ₂ on ^{MS (EI): 449 (MH} +).

2- (5-Chloro-2-methylphenyl) -3-hydroxy-3- [2- (pyrimidin-2-ylamino) -1H-benzimidazol-6-yl] -2,3-dihydro-1H-isoindole -1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.59 (m, 2H), 7.87 (d, 1H), 7.68 (m, 5H), 7.50 (s, 1H), 7.26 (m, 3H ), 7.10 (m, 1H), 7.04 (m, 1H), 6.75 (m, 1H); C 26 H 19 N 6 O 2 MS relates Cl (EI): 483 (MH ^<+> ).

3-Hydroxy-2- (3-methylphenyl) -3- [2- (pyrazin-2-ylamino) -1H-benzimidazol-6-yl] -2,3-dihydro-1H-isoindol-1-one : ¹ H NMR (400 MHz, d ₆ -DMSO): 8.57 (broad s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.83 (d, 1H), 7.56 (m, 3H), 7.43 (s, 1H), 7.27 (m, 3H), 7.11 (t, 1H), 7.09 (broads, 1H), 6.92 ( d, 1H), 6.56 (s , open), 2.15 (s, 3H); C 26 H 20 N 6 O 2 relates ^{MS (EI): 449 (MH} +).

2- (5-Chloro-2-methylphenyl) -3-hydroxy-3- [2- (pyrazin-2-ylamino) -1H-benzimidazol-6-yl] -2,3-dihydro-1H-isoindole -1-one: ¹ H NMR 400 MHz, d ₆ -DMSO): 8.56 (broads, 1H), 8.24 (s, 1H), 8.12 (d, 1H), 7.87 (d, 1H) ), 7.69 (m, 3H), 7.50 (s, 1H), 7.45 (m, 1H), 7.03-7.25 (m, 4H), 6.75 (broad s, 1H) _{), 6.56 (s, open)} ; C 26 H 19 N 6 O 2 Cl regarding ^{MS (EI): 483 (MH} +).

3-hydroxy-2- [3- (methyloxy) phenyl] -3- [2- (pyrimidin-2-ylamino) -1H-benzimidazol-6-yl] -2,3-dihydro-1H-isoindole- 1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.62 (dd, 1H), 7.83 (d, 1H), 7.53-7.62 (m, 5H), 7.28 (D, 2H), 7.20 (m, 2H), 7.14 (m, 2H), 7.04 (t, 1H), 6.56-6.69 (m, 1H), 3.61 ( _{s, 3H); C 26 H} 20 N 6 O 3 relates ^{MS (EI): 465 (MH} +).

3-hydroxy-2- [3- (methyloxy) phenyl] -3- [2- (pyrazin-2-ylamino) -1H-benzimidazol-5-yl] -2,3-dihydro-1H-isoindole- 1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 7.80 (m, 5H), 7.48-7.67 (m, 3H), 7.11-7.28 (m, 5H) , 6.78 (s, 1H), 6.58 (s, 1H), 3.74 (s, 3H); C 26 H 20 N 6 O 3 relates ^{MS (EI): 465 (MH} +).

2- (3-Chloro-2-fluorophenyl) -4,7-difluoro-3-hydroxy-3- [2- (pyrimidin-2-ylamino) -1H-benzimidazol-5-yl] -2,3- Dihydro-1H-isoindol-1-one. ¹ H NMR (400 MHz, CD ₃ OD): 8.61 (s, 1H), 8.60 (s, 1H), 7.61 (s, 1H), 7.40-7.36 (m, 3H) , 7.34 (s, 1H), 7.10-7.05 (m, 2H), 7.02 (t, J = 4.8Hz, 2H); C 25 H 14 ClF 3 N 6 O 2 for the MS (EI): 523 (MH ^<+> ).

Acetic acid 2- (3-chloro-2-fluorophenyl) -3-hydroxy-3- {2-[(4-methylpyrimidin-2-yl) amino] -1H-benzimidazol-5-yl} -2,3 -Dihydro-1H-isoindol-1-one: ¹ H NMR (400 MHz, d ₆ -DMSO): 8.45-8.41 (d, 1H), 7.89-7.85 (d, 1H), 7.69-7.58 (m, 2H), 7.51-7.46 (m, 2H), 7.35-7.28 (d, 2H), 7.20-7.14 (m, 2H) ), 6.95-6.90 (m, 2H), 5.48-5.46 (s, 1H), 1.89-1.87 (s, 3H); C ₂₆ H ₁₈ ClFN ₆ O ₂ MS (EI): 501 (MH ^<+> ).

Example 33: 2- (3-Chloro-2-fluorophenyl) -3-hydroxy-3- [2- (phenylamino) -1H-benzimidazol-5-yl] -2,3-dihydro-1H-iso Indol-1-one: 2- (3-chloro-2-fluorophenyl) -3- (3,4-diaminophenyl) -3-hydroxy-2,3-dihydro-1H-isoindol-1-one (575 mg , 1.49 mmol) in tetrahydrofuran (2.0 mL) was added 1,1′-thiocarbonyldiimidazole (400 mg, 2.25 mmol) at room temperature and stirred for 4 hours. The reaction mixture was concentrated in vacuo and the residue purified by by column chromatography (SiO _2, hexanes / ethyl acetate) 2- (3-chloro-2-fluorophenyl) -3-hydroxy-3- (2-thioxo -2 , 3-Dihydro-1H-benzimidazol-5-yl) -2,3-dihydro-1H-isoindol-1-one (530 mg, 84%) was obtained as an off-white powder. ¹ H NMR (400 MHz, d ₆ -DMSO): 12.58 (s, 1H), 12.50 (s, 1H), 7.90 (s, 1H), 7.89 (s, 1H), 7. 70-7.60 (m, 2H), 7.51 (t, 1H), 7.32 (d, 1H), 7.30 (t, 1H), 7.19 (t, 1H), 7.14 (s, 1H), 7.05 ( d, 1H), 6.94 (d, 1H); C 21 H 13 ClFN 3 O 2 S about ^{MS (EI): 426 (MH} +).

2- (3-Chloro-2-fluorophenyl) -3-hydroxy-3- (2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl) -2,3-dihydro-1H-isoindole A solution of -1-one (500 mg, 1.17 mmol) and iodomethane (200 μL, 3.20 mmol) in tetrahydrofuran (10 mL) was heated to 50 ^° C. The reaction mixture was stirred for 1 hour at which time it was cooled to room temperature. A white precipitate was collected by filtration and further rinsed with ethyl acetate (30 mL) to give 2- (3-chloro-2-fluorophenyl) -3-hydroxy-3- [2- (methylthio) -1H-benzimidazole- 5-yl] -2,3-dihydro-1H-isoindol-1-one (510 mg, 98%). ¹ H NMR (400 MHz, d ₆ -DMSO): 7.96 (br s, 1H), 7.90 (d, 1H), 7.69-7.62 (m, 2H), 7.55 (s, 1H), 7.51 (t, 1H), 7.45 (d, 1H), 7.37 (t, 1H), 7.30 (d, 1H), 7.21 (t, 1H), 7. 09 (d, 1H), 2.76 (s, 3H); C 22 H 15 ClFN 3 O 2 S about ^{MS (EI): 440 (MH} +).

2- (3-Chloro-2-fluorophenyl) -3-hydroxy-3- [2- (methylthio) -1H-benzimidazol-5-yl] -2,3-dihydro-1H-isoindol-1-one A neat solution of (50 mg, 0.114 mmol) and aniline (103 μL, 1.13 mmol) was heated at 140 ^° C. for 1 hour, at which point it was cooled to room temperature. The residue was purified by reverse phase HPLC to give 2- (3-chloro-2-fluorophenyl) -3-hydroxy-3- [2- (phenylamino) -1H-benzimidazol-5-yl] -2,3-dihydro -1H-isoindol-1-one, trifluoroacetate (8.2 mg) was obtained. C ₂₇ H ₁₈ ClFN ₄ O ₂ relates ^{MS (EI): 485 (MH} +).

Example 34: Ethyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1,3- Benzoxazol-2-yl} carbamate 2-[(4-Hydroxy-3-nitrophenyl) carbonyl] benzoic acid (9.7 g, 30 mmol) in a solution of cesium carbonate (9.8 g, 30 mmol) in DMF (100 mL) And benzyl bromide (3.6 mL, 30 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Water, 10% citric acid and ethyl acetate were added before the phases were partitioned. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (50% hexanes: 50% ethyl acetate). Product containing fractions were combined and concentrated. Impurities were removed from the solid residue by trituration with ether. The desired phenylmethyl 2-[(4-hydroxy-3-nitrophenyl) carbonyl] benzoate was obtained as a powdery yellow solid (6.17 g, 16.3 mmol, 54% yield). ¹ H NMR (400 MHz, CDCl ₃ ): 10.89 (s, 1H), 8.25 (d, 1H), 8.16 (dd, 1H), 7.91 (dd, 1H), 7.69 ( m, 1H), 7.62 (m, 1H), 7.35 (m, 1H), 7.27-7.23 (m, 3H), 7.20-7.17 (m, 2H), 7 .10 (d, 1H), 5.13 (s, 2H); C 21 H 15 NO 6 relates ^{MS (EI): 400 (MNa} +).

A solution of phenylmethyl 2-[(4-hydroxy-3-nitrophenyl) carbonyl] benzoate (5.78 g, 15.3 mmol) in acetic acid (50 mL) was added iron powder (8.5 g, 153 mmol) for 30 minutes at 50 ^° C. Processed by. After cooling to room temperature, the mixture was diluted with ethyl acetate and the solid was removed by filtration through celite. The organic filtrate is washed with saturated sodium bicarbonate, which further leads to precipitation of solid impurities. These solids were removed by filtration. The resulting organic filtrate was dried over magnesium sulfate, filtered and concentrated to a brown foam. This material was dissolved in DMF (30 mL). To this solution was added ethoxycarbonyl isothiocyanate (2.6 mL, 23 mmol). After stirring for 35 minutes, EDC (4.4 g, 23 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 35 minutes, then stirred at 65 ^° C. for 1 hour and then cooled to room temperature. To this mixture was added 10% aqueous citric acid and the resulting aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to a brown solid. Impurities were removed by grinding with methanol. The desired phenylmethyl 2-[(2-{[(ethyloxy) carbonyl] amino} -1,3-benzoxazol-5-yl) carbonyl] benzoate was added to a white solid (637 mg, 1.4 mmol, 9.4% Yield). The sample was further purified by reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ): 10.91 (br s, 1 H), 8.12 (m 1 H), 7.95 (br s, 1 H), 7.67 (m, 1 H), 7.63 -7.52 (m, 3H), 7.47-7.38 (m, 2H), 26-7.13 (m, 5H), 5.08 (s, 2H), 4.29 (q, 2H) _{), 1.38 (t, 3H)} ; C 25 H 20 N 2 O 6 relates ^{MS (EI): 445 (MH} +).

Phenylmethyl 2-[(2-{[(ethyloxy) carbonyl] amino} -1,3-benzoxazol-5-yl) carbonyl] benzoate (637 mg, 1.4 mmol) in ethyl acetate (10 mL), THF (2 mL ) And methanol (4 mL) solution was added 10% palladium-carbon (wet) (200 mg). This mixture was subjected to a 30 psi hydrogen atmosphere for 2.5 hours. The catalyst was then removed by filtration through a celite pad. The filtrate was concentrated under reduced pressure to give 198 mg of product contaminated with unidentified by-products. A portion of this material was used in the next reaction without further purification. To the impurity acid (85 mg, <0.24 mmol) was added DCM (1.8 mL), pyridine (20 μL, 0.24 mmol), and cyanuric fluoride (25 μL, 0.29 mmol). The mixture was stirred at room temperature for 30 minutes. Water and DCM were then added and the layers were partitioned. The organic extract was dried over magnesium sulfate, filtered and concentrated to a white solid (73 mg, <0.12 mmol). This solid was dissolved in dichloromethane (2 mL) and then N, N-dimethylaniline (51 mL, 0.4 mmol) and 3-chloro-2-fluoroaniline (35 mg, 0.24 mmol) were added. The mixture was heated to 75 ^° C. for 4 hours and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was purified by HPLC. Pure product-containing fractions were neutralized with saturated sodium bicarbonate. The organic solvent was distilled off under reduced pressure, and the resulting aqueous solution was extracted with ethyl acetate. The organic extract is dried over magnesium sulfate, filtered and concentrated to ethyl {5- [2- (3-chloro-2-fluorophenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H. -Isoindol-1-yl] -1,3-benzoxazol-2-yl} carbamate was obtained as a white solid (8.5 mg, 0.018 mmol). ¹ H NMR (400 MHz, d ₆ -DMSO): 11.58 (s, 1H), 7.91 (s, 1H), 7.90-7.88 (m, 1H), 7.71-7.62 (M, 2H), 7.54-7.47 (m, 3H), 7.40-7.33 (m, 2H), 7.20 (m, 1H), 7.09 (dd, 1H), 4.17 (q, 2H), 1.25 (t, 3H); C 24 H 17 ClFN 3 O 5 relating ^{MS (EI): 482,484 (MH} +).

Example 35: 5-Chloro-3-ethynyl-2-methylaniline: 4-Chloro-2-nitrotoluene (10 g, 58.3 mmol) was dissolved in concentrated sulfuric acid (60 mL) and cooled in an ice bath. N-iodosuccinimide (23.6 g, 105 mmol) was added over 0.1 hour and the cooled mixture was stirred for 2 hours. The mixture was poured into ice water (about 200 mL) and extracted twice with ethyl acetate. The combined organic portions were washed three times with 1M sodium thiosulfate solution, twice with saturated aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a tan oil (17.6 g). This was dissolved in acetic acid (80 mL). Tin (II) chloride dihydrate (52.3 g, 232 mmol) was added and the mixture was stirred for 2 hours before being concentrated in vacuo. The residue was transferred to an Erlenmeyer flask with a small amount of ethyl acetate and diluted with ether (120 mL). The mixture was stirred while cooling in an ice-water bath, and sodium hydroxide (50% aqueous solution) (60 mL) was added dropwise. The formed solid was removed by filtration and washed with hot ethyl acetate. The filtrates were combined and concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic portion was washed twice with 1N sodium hydroxide, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give an orange oil that was converted into a 75 prepacked chromatography column (gradient: hexanes to ethyl acetate). -Purification by Biotage normal phase column chromatography using hexanes 9: 1) gave 5-chloro-3-iodo-2-methylaniline as yellow crystals (7.48 g, 28.0 mmol, 47% yield). . ¹ H NMR (400 MHz, CDCl ₃ ): 7.27-7.25 (m, 1H), 6.64 (d, 1H), 3.78 (br s, 2H), 2.28 (s, 3H) ; _C 7 _H 7 ClIN relates ^{MS (EI): 268 (MH} +).

5-Chloro-3-iodo-2-methylaniline (7.44 g, 27.8 mmol) was dissolved in tetrahydrofuran (80 mL) and di-tert-butyl dicarbonate (6.37 g, 29.2 mmol) was added. The mixture was stirred at room temperature for 15 hours before a few crystalline 4-dimethylaminopyridines were added and the mixture was stirred for an additional hour. Di-tert-butyl dicarbonate (6.37 g, 29.2 mmol) was added and the mixture was stirred for an additional 56.5 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and citric acid (20% aqueous solution). The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an orange brown oil (ca. 13.5 g), diluted with acetone (100 mL). To this solution was added water (5 mL) and potassium carbonate (5 g). The mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The resulting residue was partitioned between water and ethyl acetate. The aqueous portion was extracted twice with ethyl acetate, the combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to 7.6 g, 0.02 mol (34%) of 1 , 1-Dimethylethyl (5-chloro-3-iodo-2-methylphenyl) carbamate was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): 7.79 (d, 1H), 7.11 (d, 1H), 2.28 (s, 3H), 1.41 (s, 9H); C ₁₂ H ₁₅ ClINO ₂ on ^{MS (EI): 368 (MH} +).

To a solution of 1,1-dimethylethyl (5-chloro-3-iodo-2-methylphenyl) carbamate (5 g, 13.6 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (10 mL). The solution was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous layer portion was extracted twice using ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an orange residue that was purified by column chromatography (silica gel, 5% ethyl acetate in hexane). The product was isolated to give 3.05 g, 11.4 mmol (84%) of 5-chloro-3-iodo-2-methylaniline as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): 7.26 (d, 1H), 6.64 (d, 1H), 3.78 (br s, 2H), 2.28 (s, 3H); C ₇ H ₇ MS (EI) for ClIN: 268 (MH ⁺ ).

1,1-dimethylethyl (5-chloro-3-iodo-2-methylphenyl) carbamate (610 mg, 1.7 mmol), 2-methyl-3-butyn-2-ol (245 μl, 2.5 mmol), and tri A solution of phenylphosphine (30 mg, 12 mmol) in acetonitrile (2 mL) was deoxygenated for 20 minutes. The solution was cooled to 0 ° C. and then copper (I) iodide (12 mg, 0.07 mmol) and palladium (II) dichloride (13 mg, 0.06 mmol) were added. The mixture was stirred at reflux for 1.5 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was partitioned between water and ethyl acetate. The aqueous layer portion was extracted twice using ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a brown residue which was purified by column chromatography (silica gel, 20% ethyl acetate in hexanes). The product was collected and 504 mg, 1.56 mmol (94%) of 1,1-dimethylethyl [5-chloro-3- (3-hydroxy-3-methylbut-1-in-1-yl) -2-methyl Phenyl] carbamate was obtained as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): 7.36 (d, 1H), 7.06 (d, 1H), 2.26 (s, 3H), 1.63 (s, 6H), 1.41 ( _{s, 9H); C 17 H} 22 ClNO 3 relates ^{MS (EI): 324 (MH} +).

To a toluene (3 mL) solution of 1,1-dimethylethyl [5-chloro-3- (3-hydroxy-3-methylbut-1-in-1-yl) -2-methylphenyl] carbamate (504 mg 1.56 mmol) , Potassium carbonate (215 mg, 1.56 mmol) and 18-crown-6 (82 mg, 0.31 mmol) were added. The mixture was stirred at reflux for 5 hours, then cooled to room temperature and partitioned between water and ethyl acetate. The aqueous layer portion was extracted twice using ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown residue that was purified by column chromatography (silica gel, 5% ethyl acetate in hexane). The product was collected to give 242 mg, 0.91 mmol (58%) of 1,1-dimethylethyl (5-chloro-3-ethynyl-2-methylphenyl) carbamate as a tan solid. ¹ H NMR (400 MHz, CDCl ₃ ): 7.40 (d, 1H), 7.07 (d, 1H), 3.32 (s, 1H), 2.25 (s, 3H), 1.39 ( _{s, 9H); C 14 H} 16 ClNO 2 relates ^{MS (EI): 266 (MH} +).
To a solution of 1,1-dimethylethyl (5-chloro-3-ethynyl-2-methylphenyl) carbamate (242 mg, 0.91 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (500 μl). The solution was stirred at ambient temperature for 1 hour. The solution was partitioned between saturated sodium bicarbonate and dichloromethane. The aqueous layer was extracted twice with dichloromethane. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil that was purified by column chromatography (silica gel, 50% dichloromethane in hexane). The product was collected to give 60 mg, 0.36 mmol (40%) of 5-chloro-3-ethynyl-2-methylaniline as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): 6.90 (d, 1H), 6.63 (d, 1H), 3.71 (br s, 2H), 3.24 (s, 1H), 2.23 _{(s, 3H); C 9} H 8 ClN relates ^{MS (EI): 166 (MH} +).

Example 36: 3-ethenyl-2-fluoroaniline: 1,1-dimethylethyl (3-bromo-2-fluorophenyl) carbamate (500 mg, 1.72 mmol) and 2,6-ditert-4-methylphenol ( A solution of 3 mg, 0.02 mmol) in toluene (3 mL) was deoxygenated for 10 minutes. Tetrakis (triphenylphosphine) palladium (0) (100 mg, 0.09 mmol) and tributyl (vinyl) tin (708 μl, 2.43 mmol) were added to the solution and then stirred at reflux for 4 hours. The mixture was cooled to room temperature and then filtered through a celite pad. The filtrate was concentrated under reduced pressure to give an orange residue, which was purified by column chromatography (silica gel, 5% ether in hexane). The product was isolated as a colorless oil and then diluted with dichloromethane (2 mL). To this solution was added trifluoroacetic acid (500 μl) and the solution was stirred at ambient temperature for 1 hour. The solution was partitioned between saturated sodium bicarbonate and dichloromethane. The aqueous portion was extracted twice with dichloromethane, the combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to 138 mg, 1.0 mmol (58% over 2 steps). 3-Ethenyl-2-fluoroaniline was obtained as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ): 6.92-6.82 (m, 3H), 6.71-6.66 (m, 1H), 5.80 (d, 1H), 5.35 (d , 1H); 3.72 (br s, 2H); MS (EI) for C ₈ H ₈ FN: 138 (MH ⁺ ).

Example 37: 3-ethynyl-2-fluoroaniline: A solution of 3-bromo-2-fluorobenzoic acid (18.9 g, 86.3 mmol) in thionyl chloride (125 mL) was stirred at reflux for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was azeotroped twice with benzene and then diluted with dichloromethane. The organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to give 20.3 g, 85.4 mmol (99%) of a pale yellow oil that was diluted in acetonitrile (100 mL). The solution was cooled in an ice bath and sodium azide (8.5 g, 130 mmol) was added in small portions. The mixture was stirred at ambient temperature for 1.5 hours and then concentrated under reduced pressure. The resulting residue was partitioned between water and ether. The organic portion was washed twice with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 19.9 g, 81.6 mmol (96%) of an off-white solid. This solid was dissolved in toluene (50 mL) and added dropwise to tert-butanol (100 mL) over 1 hour with stirring at 90 ° C. Upon addition, the solution was stirred at 90 ° C. for an additional 30 minutes. The solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was azeotroped twice with benzene to give 23.3 g, 80.31 mmol (93%) of 1,1-dimethylethyl (3-bromo-2-fluorophenyl) carbamate as a pale yellow solid. ¹ H NMR (400 MHz, d ₆ -DMSO): 9.21 (s, 1H), 7.63-7.58 (m, 1H), 7.42-7.37 (m, 1H), 7.11 _{-7.07 (m, 1H), 1.46} (s, 9H); C 11 H 13 BrFNO 2 relates ^{MS (EI): 291 (MH} +).

To a solution of 1,1-dimethylethyl (3-bromo-2-fluorophenyl) carbamate (15.7 g, 54.1 mmol) in triethylamine (60 mL) was added 3-methyl-butyn-2-ol (7.9 mL, 81. 2 mmol), triphenylphosphine (568 mg, 2.2 mmol), copper (I) iodide (419 mg, 2.2 mmol) and palladium (II) dichloride (767 mg, 4.33 mmol) were added. The mixture was stirred at reflux for 2 hours and then cooled to room temperature. The mixture was filtered through a silica plug and eluted with ether / hexane (1: 1). The product was isolated to give 19.4 g, 66.1 mmol (122%) of a brown oil that was diluted with toluene (60 mL). To this solution was added tert-butoxide (25 g, 270.5 mmol) and the mixture was stirred at reflux for 1 hour. The mixture was cooled to room temperature and partitioned between 20% citric acid and toluene. The aqueous layer portion was extracted twice using ethyl acetate. The combined organic portions were washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a brown residue that was purified by column chromatography (silica gel, 10% ether in hexane). The product was isolated to give 10.5 g, 44.6 mmol (83% over 2 steps) of 1,1-dimethylethyl (3-ethynyl-2-fluorophenyl) carbamate as a yellow oil. ¹ H NMR (400 MHz, d ₆ -DMSO): 9.10 (s, 1H), 7.64-7.60 (m, 1H), 7.24-7.20 (m, 1H), 7.12 −7.08 (m, 1H), 4.48 (s, 1H), 1.44 (s, 9H); MS (EI) for C ₁₃ H ₁₄ FNO ₂ : 236 (MH ⁺ ).

To a solution of 1,1-dimethylethyl (3-ethynyl-2-fluorophenyl) carbamate (10.5 g, 44.6 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (20 mL). The solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting residue was partitioned between saturated sodium bicarbonate and ether. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a brown residue. The residue was diluted with isopropanol (10 mL) and 4N HCl in dioxane (8 mL) was added. The recrystallized product was collected by vacuum filtration to give 3.7 g, 21 mmol (68%) of 3-ethynyl-2-fluoroaniline hydrochloride as a light brown solid. ¹ H NMR (400 MHz, d ₆ -DMSO): 7.08-6.91 (m, 3H), 4.45 (s, 1H); MS (EI) for C ₈ H ₆ FN: 136 (MH ⁺ ) .

Example 38: 3-Ethyl-4-fluoroaniline: To a solution of 3-ethynyl-4-fluoroaniline (220 mg, 1.62 mmol) in ethyl acetate (10 mL) was added 10% palladium-carbon (wet). The resulting mixture was subjected to a hydrogen atmosphere for approximately 1 hour. Palladium-carbon was removed by filtration through celite. The filtrate was concentrated under reduced pressure to give 3-ethyl-4-fluoroaniline (154 mg, 1.11 mmol, 69% yield) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ): 6.77 (dd, 1H), 6.50 (dd, 1H), 6.45-6.41 (m, 1H), 3.47 (brs, 2H) , 2.57 (q, 2H), 1.19 (t, 3H); C 8 H 10 FN relates ^{MS (EI): 140 (MH} +).

Example 39: 1- (3-Chloro-2-methylphenyl) ethanamine: (1Z) -1- (3-chloro-2-methylphenyl) ethanone oxime: 1- (3-chloro-2-methyl-phenyl) ) Ethanone (390 mg, 2.3 mmol) was dissolved in ethanol (6 ml) and hydroxylamine hydrochloride (433 μL, 10.4 mmol) was added. The mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer portion was extracted using ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give (1Z) -1- (3-chloro-2-methylphenyl) ethanone oxime as a yellow oil (383 mg, 2.08 mmol, 90 % Yield). ¹ H NMR (400 MHz, CDCl ₃ ): 6.95-7.37 (m, 3H), 2.36 (s, 3H), 2.26 (s, 1H), 2.21 (s, 3H); C ₉ H ₁₀ ClNO relates ^{MS (EI): 184 (MH} +).

1- (3-Chloro-2-methylphenyl) ethanamine: (1Z) -1- (3-Chloro-2-methylphenyl) ethanone oxime (383 mg, 2.08 mmol) in acetic acid (10 ml) with zinc dust ( 2.72 g, 41.6 mmol) was added and the resulting mixture was stirred at 40 ° C. for 3 hours. The reaction mixture was diluted with methanol and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was partitioned between 1N hydrochloric acid and ethyl acetate. The aqueous layer portion was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 1- (3-chloro-2-methylphenyl) ethanamine as a clear oil (290 mg, 1.7 mmol, 82% yield). ¹ H NMR (400 MHz, CDCl ₃ ): 8.98 (s, 1H), 7.11-7.44 (m, 3H), 2.37 (s, 3H), 1.81 (s, 3H); C ₉ H ₁₂ ClN relates ^{MS (EI): 170 (MH} +).

Example 40: N-ethyl-N-phenylbenzene-1,3-diamine: 1-bromo-3-nitrobenzene (500 mg, 2.5 mmol) and N-ethylaniline (375 μL, 3.0 mmol) in toluene (15 ml) Upon dissolution, sodium butoxide (193 mg, 2.0 mmol), xanthophos (143 mg, 0.25 mmol) and tris (dibenzylideneacetone) dipalladium (57 mg, 0.06 mmol) were added. The reaction mixture was stirred at 110 ° C. for 16 hours. The mixture was filtered through celite and the filtrate was concentrated to give a crude product which was purified by column chromatography (9: 1 hexanes-ethyl acetate) to give N-ethyl-3-nitro-N-phenylaniline. Obtained as a colorless oil (400 mg, 1.65 mmol, 67% yield). ¹ H NMR (400 MHz, CDCl ₃ ): 6.99-7.59 (m, 8H), 6.58-6.69 (m, 1H), 3.79 (q, 2H), 1.25 (t _{, 3H); C 14 H 14} N 2 O 2 relates ^{MS (EI): 242 (MH} +).

N-ethyl-3-nitro-N-phenylaniline (400 mg, 1.65 mmol) is dissolved in acetic acid (5 ml) at 40 ° C. and then tin (II) chloride dihydrate (1.50 g, 6.60 mmol). Was added slowly. The reaction mixture was stirred at 40 ° C. for 2 hours and further stirred at 75 ° C. for 2 hours. The mixture was concentrated under reduced pressure and the resulting residue was diluted with ether (10 ml). Aqueous sodium hydroxide (2 ml) was added dropwise to the cooled (0 ° C.) solution. The formed solid was separated by filtration and rinsed twice with hot ethyl acetate (25 ml). The filtrate was concentrated to approximately 30 ml, washed with 1N sodium hydroxide, brine, dried over sodium sulfate, and concentrated in vacuo to give N-ethyl-N-phenylbenzene-1,3-diamine as a yellow oil (117 mg, 1 0.04 mmol, 63% yield). ¹ H NMR (400 MHz, CDCl ₃ ): 6.87-7.28 (m, 7H), 6.28-6.83 (m, 2H), 3.74 (q, 2H), 3.59 (s _{, 2H), 1.20 (t,} 3H); C 14 H 16 N 2 relates ^{MS (EI): 212 (MH} +).

The following reagents were synthesized analogously:
N-methyl-N-phenylbenzene-1,3-diamine: ¹ H NMR (400 MHz, CDCl ₃ ): 6.94-7.29 (m, 8H), 6.29-6.43 (m, 3H) _{, 3.28 (s, 3H);} C 13 H 14 N 2 relates ^{MS (EI): 198 (MH} +).

N-cyclohexyl-N-methylbenzene-1,3-diamine: ¹ H NMR (400 MHz, CDCl ₃ ): 6.98-7.02 (m, 1H), 6.05-6.25 (m, 3H) , 3.49-3.57 (m, 2H), 2.73 (s, 3H), 1.10-2.05 (m, 11H); C 13 H 20 N 2 relates MS (EI): 204 ( MH ^<+> ).

Example 41: 5-Ethynyl-2-methylaniline: To a solution of 4-bromo-1-methyl-2-nitrobenzene (1.0 g, 4.6 mmol) in triethylamine (5 mL) was added 2-methyl-3-butyne- 2-ol (680 μL, 6.9 mmol), triphenylphosphine (97 mg, 0.37 mmol), copper (I) iodide (34 mg, 0.18 mmol) and palladium (II) chloride (32 mg, 0.18 mmol) were added. It was. The mixture was heated to reflux and stirred for 45 minutes. After cooling, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (65% hexanes: 35% ethyl acetate) to quantitatively give 2-methyl-4- (4-methyl-3-nitrophenyl) but-3-in-2-ol. Obtained as an orange oil. ¹ H NMR (400 MHz, CDCl ₃ ): 8.02 (d, 1H), 7.52 (dd, 1H), 7.29 (d, 1H), 2.60 (s, 3H), 1.63 ( _{s, 6H);} GCMS about _{C 12 H 13 NO 3: 219} (M +).

2-methyl-4- (4-methyl-3-nitrophenyl) but-3-yn-2-ol (1.0 g, 4.6 mmol) in acetic acid (15 mL) was added iron powder in 50 ^o C (2 .6 g, 46 mmol) was added. The mixture was stirred at 50 ^° C. for 45 minutes, after which the mixture was further heated to 70 ^° C. for 16 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, filtered through celite, and rinsed multiple times with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and saturated sodium bicarbonate, at which point a precipitate formed. The solid was removed by filtration and the filtrate was partitioned. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (50% hexane: 50% ethyl acetate) to give 4- (3-amino-4-methylphenyl) -2-methylbut-3-in-2-ol as an orange oil (509 mg, 2. 7 mmol, 58% yield in 2 steps). ¹ H NMR (400 MHz, CDCl ₃ ): 6.97 (d, 1H), 6.77 (d, 1H), 6.74 (s, 1H), 2.15 (s, 3H), 1.60 ( s, 6H); GCMS for C ₁₂ H ₁₅ NO: 189 (M ⁺ ).

A solution of 4- (3-amino-4-methylphenyl) -2-methylbut-3-in-2-ol (509 mg, 2.7 mmol) in toluene (2 mL) was treated with potassium hydroxide (1.0 g, 18 mmol). And refluxed for 20 minutes. After cooling to room temperature, water and ether were added and the layers were partitioned. The organic phase was acidified with 4N hydrochloric acid (700 μL) in dioxane. Volatiles were removed in vacuo to give a yellow / brown solid. This solid was dissolved in ether and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and carefully concentrated under reduced pressure to avoid moderate loss of volatile products. The desired 5-ethynyl-2-methylaniline was isolated as an oil in quantitative yield, but was contaminated with 10% by weight ether. ¹ H NMR (400 MHz, CDCl ₃ ): 6.99 (d, 1H), 6.85 (dd, 1H), 6.81 (d, 1H), 3.61 (br s, 2H), 2.98 (s, 1H), 2.16 ( s, 3H); GCMS about ^{_{C 9 H 9 N: 131 (}} M +).

Example 42: 1- (5-Chloro-2-thienyl) ethanamine: 1- (5-methyl-2-thienyl) ethanol (983 mg, 6.05 mmol) in toluene (12 mL) was added DBU (1.09 mL, 7.26 mmol) followed by diphenylphosphoryl azide (1.56 mL, 3.96 mmol). The resulting mixture was stirred at room temperature for 18 hours. Water and ethyl acetate were then added and the resulting biphasic mixture was partitioned. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (95% hexane: 5% ethyl acetate) to yield the desired 1- (5-chloro-2-thienyl) ethyl azide (991 mg, 5.3 mmol, 87%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ): 6.79 (m, 2H), 4.71 (q, 1H), 1.58 (d, 3H).

A mixture of 1- (5-chloro-2-thienyl) ethyl azide (991 mg, 5.3 mmol) and triphenylphosphine (1.4 g, 5.3 mmol) in THF (10 mL) and water (0.4 mL) was added at 60 ^° C. C was heated for 1 hour. After cooling to room temperature, the solution was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (90% DCM: 10% methanol) to give the desired 1- (5-chloro-2-thienyl) ethanamine (646 mg, 4.0 mmol, 75% yield) as a pink liquid. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ): 6.71 (d, 1H), 6.64 (d, 1H), 4.26 (q, 1H), 1.64 (brs, 2H), 1.44 (D, 3H).

Example 43: 5-Chloro-2,3-difluoroaniline: To acetic anhydride (20 mL) was added 2-chloro-4,5-difluoroaniline (4.7 g, 29 mmol) and the resulting solution was 100 ^° C. Stir for 1 hour. After cooling to room temperature, the mixture was stored in the refrigerator overnight. A white crystalline precipitate formed and was collected by filtration. The residual acetic anhydride was distilled off under reduced pressure. The desired N- (2-chloro-4,5-difluorophenyl) acetamide (4.69 g, 22.8 mmol, 79% yield) was isolated as a white crystalline solid. ¹ H NMR (400 MHz, CDCl ₃ ): 8.38 (dd, 1H), 7.53 (br s, 1H), 7.23 (dd, 1H), 2.25 (s, 3H); C ₈ H ₆ ClF ₂ NO on ^{MS (EI): 206 (MH} +).

A solution of N- (2-chloro-4,5-difluorophenyl) acetamide (4.69 g, 22.8 mmol) in acetic acid (4.5 mL) and concentrated sulfuric acid (15 mL) was cooled to 0 ° C. To this solution was added a mixture of fuming nitric acid (2 mL) and acetic acid (0.5 mL). After stirring at 0 ° C. for 1.5 hours, the mixture was poured into ice. The formed precipitate was collected by filtration. The filtrate was extracted with ether and the organic phase was dried over magnesium sulfate, filtered and concentrated to a sticky yellow syrup. The solid and syrup were combined and concentrated hydrochloric acid (30 mL) was added to the resulting residue. The mixture was heated to 120 ° C. for 1.25 hours. It was cooled to room temperature and subsequently poured onto ice. The aqueous solution was extracted with ethyl acetate. The organics were washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (80% hexanes: 20% ethyl acetate) to give the desired 6-chloro-3,4-difluoro-2-nitroaniline (3.30 g, 15.8 mmol, 69% yield). Got. _{^{1 H NMR (400MHz, CDCl 3}} ): 7.43 (dd, 1H), 5.86 (br s, 2H); C 6 H 3 ClF 2 N 2 O 2 relates GCMS: 208 ^(M +).

A solution of 6-chloro-3,4-difluoro-2-nitroaniline (3.30 g, 15.8 mmol) in concentrated sulfuric acid (8.3 mL) was stirred at room temperature for 3 hours and then cooled to 0 ° C. . Sodium nitrite (1.3 g, 18.8 mmol) concentrated sulfuric acid (6.7 mL) was added slowly followed by phosphoric acid (85%, 15 mL) dropwise. A blackish brown precipitate was formed and the resulting slurry was stirred at 0 ° C. for 1 hour. A suspension of copper (I) oxide (2.4 g, 30 mmol) and sodium hypophosphite hydrate (5.6 g, 64 mmol) in water (6.7 mL) was then maintained at a temperature of 0 ° C. Gradually added. Significant gas evolution was observed during the addition. When the reaction was complete, the mixture was diluted with water and ether. Celite was added to aid insoluble solid adsorption. The mixture was filtered and the filtrate was partitioned. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (90% hexanes: 10% ethyl acetate) to give the desired 5-chloro-1,2-difluoro-2-nitrobenzene (1.62 g, 8.4 mmol, 53% yield). As a yellow crystalline solid. _{^{1 H NMR (400MHz, CDCl 3}} ): 7.88 (m, 1H), 7.53 (m, 1H); C 6 H 2 ClF 2 NO 2 relates GCMS: 193 ^(M +).

To a solution of 5-chloro-1,2-difluoro-2-nitrobenzene (1.62 g, 8.4 mmol) in acetic acid (30 mL) was added tin (II) dichloride dihydrate (11.4 g, 50.4 mmol). ) Was added. The mixture was stirred at room temperature for 1.25 hours before acetic acid was removed under reduced pressure. The residue was transferred to a 500 mL Erlenmeyer flask in a minimum amount of ethyl acetate. The resulting suspension was then diluted with approximately 200 mL of ether before the flask was placed in an ice bath. A 50% aqueous sodium hydroxide solution (10 mL) was added to the vigorously stirred mixture to form a pale yellow solid. Celite and sodium sulfate were added to adsorb the precipitate and dried. All solids were removed by filtration, rinsed with ethyl acetate and discarded. The filtrate was concentrated and the residue was purified by flash chromatography (80% hexanes: 20% ethyl acetate). The desired 5-chloro-2,3-difluoroaniline was isolated as an orange oil (913 mg, 5.6 mmol, 66% yield). _{^{1 H NMR (400MHz, CDCl 3}} ): 6.57-6.52 (m, 2H), 3.91 (br s, 2H); C 6 H 4 ClF 2 N about GCMS: 163 ^(M +).

Example 44: 3-Chloro-2,6-difluoroaniline: To a solution of 3-chloro-2,6-difluorobenzoic acid (500 mg, 2.6 mmol) in DMF (7.5 mL) was added triethylamine (362 μL, 2 .6 mmol) and diphenylphosphoryl azide (560 μL, 2.6 mmol) were added. The mixture was stirred at room temperature for 1.25 hours, 2-methyl-2-propanol (2.5 mL) was added, and the mixture was heated to 90 ° C. for 2 hours. Once cooled to room temperature, the solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (80% hexanes: 20% ethyl acetate) to give 1,1-dimethylethyl (3-chloro-2,6-difluorophenyl) carbamate as a white waxy solid (approximately Mixed with 20% aniline). ¹ H NMR (400 MHz, CDCl ₃ ): 7.24 (m, 1H), 6.91 (m, 1H), 5.99 (br s, 1H), 1.51 (s, 9H); C ₁₁ H GCMS for ₁₂ ClF ₂ NO ₂ : 263 (M ⁺ ).
A solution of 1,1-dimethylethyl (3-chloro-2,6-difluorophenyl) carbamate (437 mg, 1.66 mmol) in methanol (2 mL) was treated with 4N hydrochloric acid in dioxane (2 mL) and 1 with a heat gun. Heated for minutes. After cooling, the volatile material was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with sodium bicarbonate (saturated). The organic phase was dried over magnesium sulfate, filtered and concentrated to give 3-chloro-2,6-difluoroaniline as a white solid (250 mg, 1.53 mmol, 92%). C ₆ H ₄ ClF ₂ N relates ^{MS (EI): 164 (MH} +).
Example 45: Methyl {5-[(2-{[(phenylmethyl) amino] carbonylphenyl) carbonyl] -1H-benzimido-azol-2-yl} carbamate: 2- (4-chloro-3-nitrobenzoyl) A solution of benzoic acid (5.0 g, 16.36 mmol) was heated to reflux in 28-30% aqueous ammonium hydroxide (100 mL) for 18 hours. After cooling the solution to room temperature, 6N hydrochloric acid was added until the pH reached 7. The precipitated yellow solid was collected by filtration, washed with water, and dried under reduced pressure to give 2-[(4-amino-3-nitrophenyl) carbonyl] benzoic acid (4.60 g, 98%). C ₁₄ H ₁₀ N ₂ O ₅ related to ^{MS (EI): 288 (MH} +).
A solution of 2-[(4-amino-3-nitrophenyl) carbonyl] benzoic acid (4.60 g, 16.00 mmol) in methanol (300 mL) was heated to reflux for 18 hours in the presence of a catalytic amount of concentrated sulfuric acid. The solution was cooled to room temperature and the solvent was evaporated. The yellow precipitate that formed was collected by filtration, washed with water and dried in vacuo to give methyl 2-[(4-amino-3-nitrophenyl) carbonyl] benzoate (4.8 g, quantitative). C ₁₅ H ₁₂ N ₂ O ₅ related to ^{MS (EI): 301 (MH} +).

A solution of methyl 2-[(4-amino-3-nitrophenyl) carbonyl] benzoate (420 mg, 1.39 mmol) in a mixture of terahydrofuran-ethyl acetate (1: 1, 20 mL) was added 10 Hydrogenated over% Pd-C (10 mg) for 18 hours. The catalyst was removed by filtration and the filtrate was concentrated to give methyl 2-[(3,4-diaminophenyl) carbonyl] benzoate (370 mg, 98%) as a brown powder. MS about _{C 15 H 14 N 2 O 3} (EI): 293 (M + Na).
To a solution of methyl 2-[(3,4-diaminophenyl) carbonyl] benzoate (134 mg, 0.50 mmol) in a mixture of acetonitrile-benzene (1: 1, 5 mL) was added methylisothiocyanate carbonate (70 mg, 0.60 mmol) was added followed by DCC (153 mg, 0.75 mmol) and the reaction mixture was heated to reflux for 18 hours. After cooling to room temperature, the reaction mixture was concentrated. The residue was triturated with diethyl ether (2 × 10 mL) and the pale orange solid was collected by filtration and methyl 2-[(2-{[(methoxy) carbonyl] amino} -1H-benzimidazol-5-yl). Carbonyl] benzoate (125 mg, 71%). C ₁₈ H ₁₅ N ₃ O ₅ relating MS (EI): 354 (M + H).

Methyl 2-[(2-{[(methoxy) carbonyl] amino} -1H-benzimidazol-5-yl) carbonyl] benzoate (125 mg, 0.35 mmol) was mixed with tetrahydrofuran-methanol (3: 1, 12 mL). Dissolved in the liquid, 3.0M lithium hydroxide aqueous solution (0.12 mL) was added. The solution was heated to reflux for 10 minutes, then cooled to room temperature and the solvent was concentrated. Excess hydrogen chloride (4M in dioxane) was added and the acidic mixture was concentrated to dryness. The resulting crude 2-[(2-{[(methoxy) carbonyl] amino} -1H-benzimidazol-5-yl) carbonyl] benzoic acid (120 mg) was used without further purification. C ₁₇ H ₁₃ N ₃ O ₅ relating MS (EI): 340 (M + H).

2-[(2-{[(methoxy) carbonyl] amino} -1H-benzimidazol-5-yl) carbonyl] benzoic acid (120 mg, 0.35 mmol), HOAt (0.5 M in DMF, 1.06 mL, 0 .53 mmol), N-methylmorpholine (98 μL, 0.71 mmol) and HATU (175 mg, 0.46 mmol) were added with benzylamine (64 μL, 0.60 mmol) and the reaction mixture was stirred at 60 ° C. for 18 hours. did. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in a mixture of acetonitrile-chloroform (1: 1, 50 ml), the organic phase was washed with water and brine, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (5.7 mg). C ₁₇ H ₁₃ N ₃ O ₅ relating MS (EI): 429 (M + H).

Example 46: 2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] -N- (phenylmethyl) benzamide: N, N-dimethylformamide (2. In a solution of 2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonylbenzoic acid (100 mg, 033 mmol) in (00 mL), N-methylmorpholine (0. 14 mL, 1.32 mmol) was added followed by HOAt (55 mg, 0.40 mmol) and HATU (130 mg, 0.33 mmol). The mixture was stirred at room temperature for 30 minutes before benzylamine (36 μL, 0.33 mmol) was added. The reaction mixture was then heated to 60 ° C. for 18 hours. The mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and the organic layer was washed with brine, 1.0 M hydrochloric acid, brine, saturated aqueous sodium bicarbonate and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , hexanes / ethyl acetate) to obtain the title compound (0.27 g, 80%). MS about _{C 23 H 18 N 2 O 4} (EI): 387 (M + H).

Using the same or similar synthetic methods and / or substitution with alternative reagents, the following compounds of the invention were prepared:
N-{[4- (methoxy) phenyl] methyl} -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: C ₂₄ H ₂₀ N ₂ O ₅ related to MS (EI): 399 (M -16 fragment)
N-{[3- (methoxy) phenyl] methyl} -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: C ₂₄ H ₂₀ N ₂ O ₅ relating MS (EI): 399 (M -16 fragment), 417 (M + H) .

N-[(4-Bromophenyl) methyl] -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: C ₂₃ H ₁₇ BrN ₂ O ₄ MS (EI) for: 467 (M + H).

N-[(3-bromophenyl) methyl] -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: C ₂₃ H ₁₇ BrN ₂ O ₄ MS (EI) for: 467 (M + H).

N-[(4-Chlorophenyl) methyl] -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: for C ₂₂ H ₁₅ ClN ₂ O ₄ MS (EI): 443 (M + Na).

N-[(3,4-dichlorophenyl) methyl] -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: C ₂₃ H ₁₆ Cl ₂ N MS about _{2 O 4 (EI): 455} (M + H).

N-[(4-fluorophenyl) methyl] -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: C ₂₃ H ₁₇ FN ₂ O ₄ MS (EI) for: 405 (M + H).

N-{[4-Chloro-3- (trifluoromethyl) phenyl] methyl} -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: MS about _{C 24 H 16 ClF 3 N 2} O 4 (EI): 489 (M + H).

N-[(4-methylphenyl) methyl] -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: C ₂₄ H ₂₀ N ₂ O ₄ MS (EI) for: 423 (M + Na).

N - [(3,4-dimethylphenyl) methyl] -2 - [(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] _benzamide: C _{25 H} 22 _{N 2} O ₄ relates MS (EI): 416 (M + H).

N - {[4-(dimethylamino) phenyl] methyl} -2 - [(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] _{benzamide: C} 25 _{H 23} N ₃ O ₄ relates MS (EI): 444 (M + Na).

2 - [(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl]-N-(3-phenylpropyl) _{benzamide: C 25 H 22 N 2 O} 4 relates MS ( EI): 437 (M + Na).

2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] -N- (2-phenylethyl) benzamide: MS for C ₂₄ H ₂₀ N ₂ O ₄ ( EI): 401 (M + H), 384 (M-16 fragment); ¹ H NMR (400 MHz, d ₆ -DMSO): 10.60 (s, 1H), 7.76 (d, 1H), 7.58 ( dd, 2H), 7.12-7.36 (m, 6H), 6.85 (m, 3H), 4.54 (s, 2H), 3.52 (m, 1H), 3.16 (m , 1H), 2.82 (m, 1H), 2.62 (m, 1H).
2 - [(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] -N- _{phenyl-benzamide: C 22 H 16 N 2 O} 4 relates MS (EI): 373 ( M + H).

N- (3-Chlorophenyl) -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: MS (EI for C ₂₂ H ₁₅ ClN ₂ O ₄ ): 429 (M + Na).

N- (4-chlorophenyl) -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: MS (EI for C ₂₂ H ₁₅ ClN ₂ O ₄ ): 407 (M + H).

N- butyl-2 - [(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] _{benzamide: C 20 H 20 N 2 O} 4 relates MS (EI): 353 ( M + H).

N- (1-methylethyl) -2-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) carbonyl] benzamide: MS for C ₁₉ H ₁₈ N ₂ O ₄ ( EI): 361 (M + Na).

In general, the compounds listed above were identified and / or isolated by LC-MS and characterized by ¹ H-NMR (most typically 400 MHz). Liquid chromatography-mass spectrometry (LC-MS) analysis was performed using at least one of the following: Hewlett-Packard Series 1100 MSD, Agilent 1100 Series LC / MSD (available from Agilent Technologies Deutschland Deutschland Deutschland, Germany). ) Or Waters 8-Channel MUX System (obtained from Waters Corporation, Milford, Mass.). Compounds were identified by either their observed mass [M + 1] ion (positive mode) or [M-1] ion (negative mode). ¹ H-NMR data for the compounds was obtained by a Varian AS400 Spectrometer (400 MHz, obtained from Varian GmbH, Darmstadt, Germany).

  Additional examples of compounds made by the above methods and procedures are listed in Table 1. Each of these compounds is a further aspect of the invention.

(Assay)
For activity assays, Raf, or a compound of the invention, is generally non-diffusively bound to an insoluble support (eg, microtiter plate, array, etc.) having an isolated sample receiving site. The insoluble support can be made from any composition to which the composition can be bound, easily separated from the soluble material, and otherwise compatible with the overall screening method. The surface of such a support may be solid or porous and is of any convenient shape. Examples of suitable insoluble supports include microtiter plates, arrays, membranes and beads. These are typically made from glass, plastic (eg polystyrene), polysaccharides, nylon or nitrocellulose, Teflon ™, and the like. Microtiter plates and arrays are particularly convenient because a large number of assays can be performed simultaneously using small amounts of reagents and samples. The particular mode of binding of the composition is not critical as long as it is compatible with the reagents and methods of the present invention, maintains the activity of the composition and is non-diffusible. Examples of binding methods include the use of antibodies (which do not sterically interfere with the ligand binding site or activation sequence when the protein is bound to the support), “adhesive” or direct to the ionic support. Binding, chemical crosslinking, synthesis of proteins or reagents on the surface, and the like. After protein or reagent binding, excess unbound material is removed by washing. The sample receiving site can then be blocked by incubation with bovine serum albumin (BSA), casein or other non-noxious proteins or other moieties.

One measure of inhibition is Ki. For compounds with an IC ₅₀ of less than 1 μM, K _i or K _d is defined as the dissociation rate constant for the interaction of the drug with Raf. Typical compositions contain, for example, less than about 100 [mu] M, less than about 10 [mu] M, has a _{K i} of less than about 1 [mu] M, further, for example, less than about 100 nM, further have a _{K i} less than about 10 nM. The K _i of a compound is determined from an IC ₅₀ based on three assumptions. First, only one type of compound molecule binds to the enzyme and there is no cooperative action. Second, the concentrations of active enzyme and test compound are known (ie there are no significant amounts of impurities in the preparation). Third, the enzymatic rate of the enzyme-inhibitor complex is zero. The rate data (ie compound concentration) is the equation:

Where V is the observed rate, V _max is the rate of the free enzyme, I ₀ is the inhibitor concentration, E ₀ is the enzyme concentration, and K _d is the dissociation constant of the enzyme-inhibitor complex. .

Another measure of inhibition is the GI ₅₀ defined as the compound concentration that results in a 50 percent reduction in cell growth rate. Representative compounds are, for example, less than about 1 mM, less than about 10 [mu] M, has a _{GI 50 's} of less than about 1 [mu] M, further, for example, less than about 100 nM, further comprises _{GI 50' s} of less than about 10 nM. Measurement of GI ₅₀ is performed using a cell proliferation assay.

Tyrosine kinase activity is determined by 1) measurement of kinase-dependent ATP consumption by luciferase / luciferin-mediated chemiluminescence in the presence of common substrates such as polyglutamine, tyrosine (pEY), or 2) well surface of polystyrene microtiter plates As determined by the incorporation of ³³ P-ATP-derived radioactive phosphate into a generic substrate adsorbed on the surface. The phosphorylated substrate product is quantified by scintillation spectroscopy.

(Luciferase-coupled chemiluminescence assay protocol)
Kinase activity is measured as a percent of ATP consumed after the kinase reaction using luciferase-luciferin coupled chemiluminescence. Reactions were performed in 384 well, white, media-bound microtiter plates (Greiner). Test compounds, ATP and kinase were adjusted to a 20 uL volume to initiate the kinase reaction. The reaction mixture was incubated at room temperature for 3 hours. For c-Raf, B-Raf, and B-RafV599E, 2.5-5 nM enzyme with compound in 20 mM Tris pH 7.5, 10 mM MgCl2, 0.03% TX-100, and 1 mM DTT at room temperature. Pre-incubated for 30 minutes. After the kinase reaction, a 20 μL aliquot of the luciferase-luciferin mixture was added and the chemiluminescence signal was measured using a Victor ² plate reader (Perkin Elmer). The luciferase-luciferin mixture is 50 mM HEPES, pH 7.8, 67 mM oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100, 0.25 mg / mL coenzyme A, 63 μM Of AMP, 28 μg / mL luciferin and 40,000 units / mL luciferase. Total ATP consumption is limited to 25-60% and IC ₅₀ values correlate well with those determined by radiometric assays.

⁽³³ P- phosphoryl transfer Kinase Assay Protocol II)
In the following method, direct c-Raf kinase activity was measured as incorporated ³³ P. Reactions were performed in 96 well polypropylene V bottom plates. Samples were incubated for 30 minutes before being transferred to 96 well P81 Unifilter plates (Whatman). Each reaction was mixed with 5 μM ATP and ³³ P-γ-ATP (3.3 μCi / nmol) in 20 mM Tris, pH 7.5, 10 mM MgCl 2, 0.03% TX-100, and 1 mM DTT. 50 nM c-Raf. The plate was washed 10 times with 0.075% phosphoric acid. 100 μl of scintillation fluid was added and the incorporated ³³ P was measured by liquid scintillation spectroscopy using a MicroBeta scintillation counter (Perkin Elmer).

(Structural activity relationship)
Table 1 shows structure activity relationship data for selected compounds of the present invention. Inhibition using the following legend, indicated as _{IC 50:} A = _{IC 50} less than 100 nM, B = 100 nM than it is, 1000 nM following _IC 50, C = 1000 nM greater but but, 10,000 nM following _{IC 50,} IC _{50 with} D = 10,000 nM or more. Blanks simply indicate a lack of data.

As discussed above, compound names were generated using a naming authority issued by ACD / Labs, Toronto, Canada. To further illustrate the compounds of the present invention, representative ones of the compounds listed in Table 1 are shown in Table 2 below, which shows the structure of the compound as well as the names created by the naming authority. These examples are provided to further clarify the compounds of the present invention.

It will be appreciated that the present invention, as well as the manner and method of carrying out and using the present invention, are sufficiently clear, concise and concise so that any person skilled in the art can practice and use the present invention. And explained here in precise terms. While the foregoing describes preferred embodiments of the present invention, it should be understood that modifications can be made to the present invention without departing from the spirit or scope of the invention as set forth in the claims. It is. In order to more particularly point out and distinctly claim the subject matter of the invention relating to the present invention, the conclusion of the specification lies in the appended claims.

Claims (13)

Formula IX,
Or a pharmaceutically acceptable salt thereof,
A is ortho-phenylene;
n is 0 to 3;
Each of R ¹ is —H, halogen, —CN, —NO ₂ , —OR ³ , —N (R ³ ) R ³ , —S (O) _{0 to 2} R ³ , —SO ₂ N (R ³ ). R ³ , —CO ₂ R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) SO ₂ R ³ , —N (R ³ ) C (O) R ³ , —N (R _{^{3) CO 2 R 3, -C}} (O) R 3, -OC (O) R 3, aryl aryl, optionally substituted substituted _{C 1 to 6} alkyl, optionally substituted optionally Independently selected from C _1-6 alkyl, optionally substituted heterocycle, and optionally substituted heterocycle C _1-6 alkyl;
Z is -N =, X is, -N ^(R 2) -, and -O- pressurized et is selected;
Y is, -C ^(R 2) = a and;
Each of R ² is R ³ , —C (O) N (R ³ ) R ³ , —N (R ³ ) CO ₂ R ³ , —N (R ³ ) C (O) N (R ³ ) R ³ , And —N (R ³ ) C (O) R ³ ;
Each R ^3, -H, heterocycle substituted C _{1 to 6} alkyl which is optionally substituted, aryl which is optionally substituted, aryl C _{1 to 3} alkyl which is optionally substituted, optionally And optionally selected from optionally substituted heterocycle C _1-3 alkyl;
Any two R ³ , when taken together with the common nitrogen to which they are attached, form an optionally substituted 5- to 7-membered heterocycle, said optionally substituted The 5- to 7-membered heterocycle optionally contains at least one additional heteroatom selected from N, O, S, and P;
R ⁴ is selected from —H, —OH, optionally substituted C _1-6 alkyl and optionally substituted C _1-6 alkoxy;
Each optionally substituted alkyl, aryl, and heterocyclic group is C _1-6 alkyl, aryl, aryl C _1-6 alkyl, heterocyclic C _1-6 alkyl, heterocyclic, alkoxy, amino, amidino , Aryloxy, arylalkyloxy, carboxy, acyloxy, carboxyalkyl, carboxamide, benzyloxycarbonylamino, cyano, acyl, halogen, hydroxy, nitro, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, thiol, oxo, carbamyl, acylamino, hydrazino Can be independently substituted with 1 to 3 groups selected from:
Compound. A claim wherein R ¹ is -H; Z is -N =; Y is -C (R ² ) =; and X is selected from -N (R ² )-and -O-. 1 or a pharmaceutically acceptable salt thereof. Formula Xa or Xb,
Or a pharmaceutically acceptable salt thereof.
In which A is orthophenylene;
When R ² is —H or optionally substituted C _1-6 alkyl, R ² is —H and all other groups are identical, then of course Xa and Xb are single molecules Represents a tautomer of
R ³ is —H, optionally substituted C _1-6 alkyl, optionally substituted aryl, optionally substituted aryl C _1-3 alkyl, optionally substituted heterocycle, and Selected from optionally substituted heterocycle C _1-3 alkyl;
R ^3a is either —H or optionally substituted C _1-6 alkyl;
R ^3b is optionally substituted C _1-6 alkyl, optionally substituted aryl, optionally substituted aryl C _1-3 alkyl, optionally substituted heterocycle, and optionally substituted Selected from heterocyclic C _1-3 alkyl being substituted;
R ⁴ is selected from —H, —OH, optionally substituted C _1-6 alkyl and optionally substituted C _1-6 alkoxy; and each optionally substituted alkyl group, aryl group , And heterocyclic groups are C _1-6 alkyl, aryl, aryl C _1-6 alkyl, heterocyclic C _1-6 alkyl, heterocyclic, alkoxy, amino, amidino, aryloxy, arylalkyloxy, carboxy, acyloxy, 1 selected from carboxyalkyl, carboxamide, benzyloxycarbonylamino, cyano, acyl, halogen, hydroxy, nitro, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, thiol, oxo, carbamyl, acylamino, hydrazino, hydroxyamino, and sulfonamide Independently 3 to 3 groups may be substituted,
Compound. R ³ is aryl which is optionally substituted; R ^3a is located at -H; and R ² is -H, a compound or a pharmaceutically acceptable salt thereof according to claim 3. Formula XI,
Or a pharmaceutically acceptable salt thereof.
Wherein R ³ is aryl disubstituted with alkyl and halogen; and R ^3b is optionally substituted C _1-6 alkyl, optionally substituted aryl, and optionally substituted. Selected from aryl C _1-3 alkyl
Compound. The compound of claim 1, wherein:
Or a compound selected from pharmaceutically acceptable salts of any of the above compounds. A composition comprising the compound of claim 1 and at least one pharmaceutically acceptable carrier or excipient. A composition that inhibits the in vivo activity of Raf kinase, comprising a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof. 2. A composition for the treatment or inhibition of a disease or disorder associated with uncontrolled cellular activity, abnormal cellular activity, and / or undesirable cellular activity, wherein the therapeutically effective amount of at least one of claim 1 Or a pharmaceutically acceptable salt thereof. The compound has the following structure:
Methyl {5- [2- (5-chloro-2-methylphenyl) -1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl] -1H-benzimidazole- 7. The compound of claim 6, which is 2-yl} carbamate, or a pharmaceutically acceptable salt thereof. A composition for the treatment of solid tumors, comprising a therapeutically effective amount of a compound according to claim 10 or a pharmaceutically acceptable salt thereof. Rheumatoid arthritis in mammals, graft host disease, multiple sclerosis, psoriasis, atherosclerosis, myocardial infarction, ischemia, pulmonary hypertension, stroke, restenosis, mesenteric disease, osteoarthritis, macular degeneration, Or a composition for the treatment of diabetic retinopathy, comprising a therapeutically effective amount of a compound according to claim 10 or a pharmaceutically acceptable salt thereof. A composition comprising a compound according to claim 10 and at least one pharmaceutically acceptable carrier or excipient.